Quinoline sulfonamide compounds and their use as antibacterial agents

ABSTRACT

The invention provides novel quinoline sulfonamide compounds of Formula I: 
                         
and their use for the treatment or prevention of bacterial infections caused by both Gram positive and Gram negative bacteria such as, for example, infections caused by one or more bacteria from the Enterobactericeae, Staphylococcaceae, or Streptococcaceae families. The compounds described and claimed herein may be formulated in one or more pharmaceutical or veterinary compositions for use in animal husbandry, and in particular in relation to the treatment of mastitis by directly targeting mastitis causing bacteria in a bovine herd. In certain embodiments described herein the pharmaceutical or veterinary compositions are formulated as a spray for direct administration to the udder of the bovine animal such as a cow.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 national phase of PCT/NZ2018/050182, filed Dec. 20, 2018, which claims the benefit of the filing date of U.S. Application No. 62/608,141, filed Dec. 20, 2017, the disclosures of which are incorporated, in their entirety, by this reference.

TECHNICAL FIELD

The invention relates to quinoline sulfonamide compounds and their use for the treatment or prevention of bacterial infections. In particular, the invention relates to novel sulfonamide quinoline compounds substituted at the 2-position of the quinoline ring.

BACKGROUND OF THE INVENTION

Bacterial Infections in humans and other animals continue to present a threat to human and animal health and well-being. Despite the evolution of several classes of antibiotics over the last century, bacterial resistance to commonly used antibiotics is a globally recognised problem to which there are few solutions at present.

Antibiotic resistance is present in every country. In February 2017, the World Health Organisation listed priority human pathogens for which research and development of new antibiotics is most critical, these being Acinetobacter baumannii (carbapenem-resistant), Pseudomonas aeruginosa (carbapenem-resistant), and Enterobacteraceae (carbapenem-resistant, ESBL-producing). Animals, particularly in food production, are also susceptible to a wide range of bacterial infections, e.g. Gram-negative respiratory disease, foot-rot, and mastitis including acute E. coli mastitis, and Pseudomonas mastitis. In New Zealand, dairy cattle, antibiotics are used primarily during dry cow therapy and for the treatment of mastitis, where the most commonly used antibiotics are penicillin-based products. Worldwide the widespread use of antibiotics in animal food has driven the rise of antibiotic-resistant strains of bacteria.

Antibiotics are used in livestock production for both disease prevention and treatment of disease. Approximately 80% of the antibiotics used in the United States is through their use in the animal food industry, and many of these antibiotics are important in human medicine. While the development of antibiotic resistance by bacteria is a natural process, the widespread use of antibiotics in the animal food and agricultural industries raises the possibility of antibiotic-resistant bacteria of animal origin contributing to infections in humans. As such, it is crucial that new antibacterial agents are developed that are targeted specifically at the agricultural industry, to protect the use of essential human antibiotics.

One example of a problematic bacterial infection in animals is bovine mastitis, a bacterial infection of the udder. Bovine mastitis is the most significant production limiting disease for dairying worldwide, and costs the New Zealand dairy industry NZ$280M each year. Bovine mastitis is not only a disease of economic importance, but one with possible implications for public health. Mastitis is recognised as the most common reason for antibiotic use in the dairy industry, both within New Zealand and worldwide.

Preventative teat sprays containing sanitisers such as chlorhexidine and iodine are vital tools in managing mastitis. These sanitisers are applied to cows after every milking. However, chlorhexidine and iodine are essential human medicines used for the control of infection. They appear on the World Health Organisation (WHO) Model List of Essential Medicines. As bacterial tolerance to chlorhexidine has already been reported in Staphylococcus aureus, Klebsiella pneumonae, and Pseudomonas aeruginosa, it is crucial that new non-medical alternative sanitisers are developed for use in the agricultural industry.

An ionophore is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across a cell membrane. An ionophore binds a metal, transports it across a lipid bilayer, releases the metal, and then re-engages with metal ions not yet transported across the membrane, repeating the process. Ionophores have been used as growth promotants in agriculture for decades. Monensin is the most widely used, and is included in animal feed to improve weight gain of beef cattle through a mechanism that alters rumen fermentation, in turn increasing milk yield and reducing milk fat content. Current evidence indicates that ionophores are unlikely to contribute to the spread of antibiotic resistance in humans because ionophores are not used in human medicine and have a distinct mode of action compared to antibiotic used in humans.

In the search for improved antibacterial agents, the applicant has found that ionophores able to bind zinc are potential candidates because they show rapid killing of certain bacteria. Notably, these bacteria are mastitis-causing bacteria and ionophores that bind zinc are not used in human medicine to treat bacterial infections. Taking advantage of zinc as a means to control mastitis offers two advantages: zinc homeostasis is critical to bacterial survival, and excess zinc accumulation in bacteria results in cellular toxicity.

8-Hydroxy quinoline compounds are examples of ionophores. They have the general structure:

They are known to have varied antibacterial activity against a number of clinically-relevant bacterial species, including E. coli, S. aureus, C. difficile, S. mutans, and Mycobacterium species. The acidic phenolic hydrogen is thought to be important for activity because it can be ionised relatively easily. Adding electron withdrawing substituents to the phenol ring (e.g. chlorine atoms) decreases the pK_(a) of the phenolic hydrogen and can affect antibacterial activity. Sulfonamide quinoline compounds (where the hydroxyl group of the phenol ring has been replaced with a sulfonamide group) are also effective as antibacterial agents through their ionophore activity. The pK_(a) of the sulfonamide hydrogen can be tailored by changing the substituent on the sulfonamide moiety.

Examples of known 8-sulfonamide quinoline compounds include:

The applicant has now found that certain substituted sulfonamide quinoline compounds exhibit inhibitory (antibacterial) activity against several groups of bacteria (including Gram-positive and Gram-negative bacteria). It is therefore an object of the invention to provide novel quinoline compounds as potential antibacterial agents, or to at least provide a useful alternative to current antibiotics.

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided a compound of Formula I:

wherein

R₁ is selected from the group comprising alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxyaryl, heterocyclyl, alkylheterocyclyl, alkoxyheterocyclyl, heteroaryl, alkylheteroaryl, alkoxyheteroaryl, C₁-C₆ alkyl(cycloalkyl), aralkyl, C₁-C₆ alkyl(alkylaryl), C₁-C₆ alkyl(alkoxyaryl), C₁-C₆ alkyl(heterocyclyl), C₁-C₆ alkyl(alkylheterocyclyl), C₁-C₆ alkyl(alkoxyheterocyclyl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(alkylheteroaryl), and C₁-C₆ alkyl(alkoxyheteroaryl), each of which is optionally substituted with one or more of halogen, OR₃, OCHO, OC(═O)R₃, SR₃, SCF₃, SC(═O)R₃, S(═O)R₃, SO₂R₃, SO₃H, SO₂NR₃R₄, NR₃R₄, NR₃CHO, NR₃COR₄, NR₃CO₂R₄, NR₃SO₂R₄, NO₂, CN, CHO, COR₃, CO₂H, CO₂R₃, and CONR₃R₄;

R₂ is selected from the group comprising alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxyaryl, heterocyclyl, alkylheterocyclyl, alkoxyheterocyclyl, heteroaryl, alkylheteroaryl, alkoxyheteroaryl, C₁-C₆ alkyl(cycloalkyl), aralkyl, C₁-C₆ alkyl(alkylaryl), C₁-C₆ alkyl(alkoxyaryl), C₁-C₆ alkyl(heterocyclyl), C₁-C₆ alkyl(alkylheterocyclyl), C₁-C₆ alkyl(alkoxyheterocyclyl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(alkylheteroaryl), C₁-C₆ alkyl(alkoxyheteroaryl), (C₁-C₆ alkyl)NR₇R₈, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₈R₉, (C₁-C₆ alkyl)N((C₁-C₆ alkyl)NR₈R₉)₂, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)OR₈, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)O(C₁-C₆ alkyl)OR₈, (C₁-C₆ alkyl)NR₇C(═O)R₈, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)C(═O)NR₈R₉, (C₀-C₃ alkyl)CH═NOR₇, CH═NNR₇R₈, (C₀-C₃ alkyl)CH═NNR₇R₈, (C₀-C₃ alkyl)CH═NNR₃C(═O)R₇, (C₀-C₃alkyl)CH═NNR₃C(═S)R₇, (C₀-C₃alkyl)CH═NNR₃C(═O)NR₇R₈, (C₀-C₃ alkyl)CH═NNR₃C(═S)NR₇R₈, (C₀-C₃ alkyl)CH═NNR₃C(═O)C(═NOR₇)R₈, (C₀-C₃ alkyl)CH═NR₃C(═O)C(═O)NR₇R₈, (C₀-C₃ alkyl)C(═O)NR₇R₈, (C₀-C₃ alkyl)C(═O)NR₃OR₇, (C₀-C₃ alkyl)C(═O)NR₃NR₇R₈, each of which is optionally substituted with one or more of each of halogen, alkyl, OR₃, OCHO, OC(═O)R₃, SR₃, SC(═O)R₃, S(═O)R₃, S₂R₃, SO₃H, SO₂NR₃R₄, NR₃R₄, NR₃CHO, NR₃COR₄, NR₃CO₂R₄, NR₃C(═O)NR₄R₅, NR₃C(═S)NR₄R₅, NR₃C(═NR₄)NR₅R₆, NR₃C(═NNO₂)NR₄R₅, NR₃C(═NCN)NR₄R₅, NR₃C(═CHNO₂)NR₄R₅, NR₃C(═NR₄)R₅, NR₃SO₂R₄, NO₂, CN, CHO, COR₃, CO₂H, C₂R₃, CONR₃R₄, C(═O)NR₃OR₃, C(═O)NR₃NR₄R₅, C(═O)NR₃CN, or wherein R₂ is CHO;

R₃, R₄, R₅ and R₆ are each selected from the group comprising hydrogen, alkyl, aryl and aralkyl; and

R₇, R₈ and R₉ are each selected from the group comprising hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxyaryl, heterocyclyl, alkylheterocyclyl, alkoxyheterocycyl, heteroaryl, alkylheteroaryl, alkoxyheteroaryl, C₁-C₆ alkyl(cycloalkyl), aralkyl, C₁-C₆ alkyl(alkylaryl), C₁-C₆ alkyl(alkoxyaryl), C₁-C₆ alkyl(heterocyclyl), C₁-C₆ alkyl(alkylheterocyclyl), C₁-C₆ alkyl(alkoxyheterocyclyl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(alkylheteroaryl), C₁-C₆ alkyl(alkoxyheteroaryl), monosaccharide, disaccharide, each of which is optionally substituted with one or more of halogen, OR₃, OCHO, OC(═O)R₃, SR₃, SC(═O)R₃, S(═O)R₃, SO₂R₃, SO₃H, SO₂NR₃R₄, NR₃R₄, NR₃CHO, NR₃COR₄, NR₃CO₂R₄, NR₃C(═O)NR₄R₅, NR₃C(═S)NR₄R₅, NR₃C(═NR₄)NR₅R₆, NR₃C(═NNO₂)NR₄R₅, NR₃C(═NCN)NR₄R₅, NR₃C(═CHNO₂)NR₄R₅, NR₃C(═NR₄)R₅, NR₃S₂R₄, NO₂, CN, CHO, COR₃, CO₂H, CO₂R₃, CONR₃R₄, C(═O)NR₃OR₃, C(═O)NR₃NR₄R₅, C(═O)NR₃CN; or a pharmaceutically acceptable salt or hydrate thereof.

In certain embodiments, R₂ is not an unsubstituted group selected from the following: methyl, pyridyl, formyl, 1-2-[(1-ethyl-6,7-dimethoxy-4-isoquinolinyl)methyl, 3-(trifluoromethyl)phenyl, 3-(trifluoromethoxy)phenyl, or 3,5-dimethyl-1H-pyrazol-1-yl.

In certain embodiments, where R₁ is an unsubstituted aminosulfonylphenyl, R₂ is not unsubstituted 2-(diethylamino)ethyl.

In certain embodiments the compound is a compound of Formula I wherein R₁ and R₂ are not both unsubstituted groups selected from: alkyl, alkenyl, alkynyl, or aryl.

In certain embodiments, the compound defined by Formula I is not Benzenesulfonamide, 4-hydroxy-N-(2-methyl-8-quinolinyl); 2-Thiophenesulfonamide, 4-bromo-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 4-(1-methylethoxy)-N-(2-methyl-8-quinolinyl); Ethanesulfonamide, N-[2-[(1-ethyl-6,7-dimethoxy-4-isoquinolinyl)methyl]-8-quinolinyl]; Methanesulfonamide, N-[2-[(1-ethyl-6,7-dimethoxy-4-isoquinolinyl)methyl]-8-quinolinyl]; Methanesulfonamide, N-(2-formyl-8-quinolinyl); Benzenesulfonamide, 3-fluoro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 2-fluoro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 3-bromo-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 3-chloro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 2-chloro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 2-bromo-N-(2-methyl-8-quinolinyl); 3-Pyridinesulfonamide, N-(2-methyl-8-quinolinyl); 2-Thiophenesulfonamide, 5-methyl-N-(2-methyl-8-quinolinyl); 2-Thiophenesulfonamide, 3-methyl-N-(2-methyl-8-quinolinyl); 2-Thiophenesulfonamide, 5-ethyl-N-(2-methyl-8-quinolinyl); 3-Thiophenesulfonamide, 2,5-dichloro-N-(2-methyl-8-quinolinyl); 2-Thiophenesulfonamide, 4-bromo-5-chloro-N-(2-methyl-8-quinolinyl); 2-Furansulfonamide, N-(2-methyl-8-quinolinyl); 2-Thiophenesulfonamide, 4,5-dibromo-N-(2-methyl-8-quinolinyl); 2-Thiophenesulfonamide, 5-chloro-N-(2-methyl-8-quinolinyl)-4-nitro; 2-Thiophenesulfonamide, 4,5-dichloro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 4-amino-2-fluoro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 4-amino-2-methoxy-N-[2-(2-pyridinyl)-8-quinolinyl]; Methanesulfonamide, N-[2-(2-pyridinyl)-8-quinolinyl]; Benzenesulfonamide, 2-methoxy-4-nitro-N-[2-(2-pyridinyl)-8-quinolinyl]; 2-Thiophenesulfonamide, 5-bromo-N-[2-(2-pyridinyl)-8-quinolinyl]; Benzenesulfonamide, 4-cyano-N-[2-(2-pyridinyl)-8-quinolinyl]; Benzoic acid, 3-[[[2-(2-pyridinyl)-8-quinolinyl]amino]sulfonyl]; Benzenesulfonamide, 3,5-difluoro-N-[2-(2-pyridinyl)-8-quinolinyl]; Benzoic acid, 2-[[[2-(2-pyridinyl)-8-quinolinyl]amino]sulfonyl]-, methyl ester; Benzenesulfonamide, N-[2-(2-pyridinyl)-8-quinolinyl]-4-(trifluoromethyl); Benzenesulfonamide, N-[2-(2-pyridinyl)-8-quinolinyl]; Benzenesulfonamide, 4-chloro-N-[2-(2-pyridinyl)-8-quinolinyl]; Benzenesulfonamide, 4-methyl-N-[2-(2-pyridinyl)-8-quinolinyl]; 2-Pyridinesulfonamide, N-[2-[3-(trifluoromethyl)phenyl]-8-quinolinyl]; 1-Piperazinesulfonamide, N-[2-[3-(trifluoromethoxy)phenyl]-8-quinolinyl]; 1-Pyrrolidinesulfonamide, N-[2-[3-(trifluoromethoxy)phenyl]-8-quinolinyl]; Benzenesulfonamide, 3,5-dichloro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 2-amino-4-fluoro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 4-fluoro-N-(2-methyl-8-quinolinyl)-2-nitro; 2-Thiophenesulfonamide, 5-bromo-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 2-amino-N-(2-methyl-8-quinolinyl)-4-(trifluoromethyl); Benzenesulfonamide, 2-amino-4-methoxy-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 4-hydroxy-N-(2-methyl-8-quinolinyl)-2-nitro; 2-Thiophenesulfonamide, 5-chloro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 2-amino-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 2-methyl-N-(2-methyl-8-quinolinyl)-5-nitro; Benzenesulfonamide, 4-methoxy-N-(2-methyl-8-quinolinyl)-2-nitro; Benzenesulfonamide, N-(2-methyl-8-quinolinyl)-2-nitro-4-(trifluoromethyl); Benzenesulfonamide, N-(2-methyl-8-quinolinyl)-3-nitro; Benzenesulfonamide, 2-methoxy-5-methyl-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 4-amino-N-(2-methyl-8-quinolinyl); 8-Quinolinesulfonamide, N-(2-methyl-8-quinolinyl); Benzenesulfonamide, N-(2-methyl-8-quinolinyl)-2-nitro; Benzenesulfonamide, 4-fluoro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 4-chloro-N-(2-methyl-8-quinolinyl); Acetamide, N-[4-[[(2-methyl-8-quinolinyl)amino]sulfonyl]phenyl]; Acetamide, N-[4-[[[2-[2-(diethylamino)ethyl]-8-quinolinyl]amino]sulfonyl]phenyl]; Benzenesulfonamide, N-(2-formyl-8-quinolinyl); Methanesulfonamide, N-[2-(3,5-dimethyl-1Hpyrazol-1-yl)-8-quinolinyl]; Benzenesulfonamide, N-[2-(3,5-dimethyl-1Hpyrazol-1-yl)-8-quinolinyl]-4-methyl; Methanesulfonamide, 1,1,1-trifluoro-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 4-methoxy-N-(2-methyl-8-quinolinyl); Methanesulfonamide, N-(2-methyl-8-quinolinyl); Benzenesulfonamide, 2,4,6-trimethyl-N-(2-methyl-8-quinolinyl); Benzenesulfonamide, N-(2-methyl-8-quinolinyl) and Benzenesulfonamide, 4-methyl-N-(2-methyl-8-quinolinyl).

In certain embodiments, the compounds defined by Formula I are not ZDR030, ZDR035, ZDR046, ZDR090, ZDR102, ZDR111, ZDR112, ZDR113, ZDR114, ZDR115, ZDR116, ZDR117, ZDR119, ZDR120, ZDR121, ZDR122, ZDR124, ZDR125, ZDR143, ZDR167, ZDR170, ZDR171, ZDR187, ZDR261, ZDR262, ZDR266, ZDR268 and ZDR269, as disclosed herein.

In certain embodiments according to the compounds defined by Formula I, R₁ is alkyl, aryl, alkylaryl, alkoxyaryl or heteroaryl substituted with halogen.

In certain embodiments R₁ is aryl, alkylaryl or alkoxyaryl substituted with halogen.

In certain embodiments R₁ is alkylaryl or alkoxyaryl substituted with halogen.

In certain embodiments R₁ is alkylaryl substituted with halogen. For example, R₁ may be (trifluoromethyl)phenyl.

In certain embodiments R₂ is (C₁-C₆ alkyl)NR₇R₈.

In certain embodiments R₁ is alkyl, aryl, alkylaryl, alkoxyaryl or heteroaryl substituted with halogen and R₂ is (C₁-C₆ alkyl)NR₇R₈.

In certain embodiments R₁ is aryl, alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₁-C₆ alkyl)NR₇R₈.

In certain embodiments R₁ is alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₁-C₆ alkyl)NR₇R₈

In certain embodiments R₁ is alkylaryl substituted with halogen and R₂ is (C₁-C₆ alkyl)NR₇R₈.

In certain embodiments R₁ is (trifluoromethyl)phenyl and R₂ is (C₁-C₆ alkyl)NR₇R₈.

In certain embodiments R₂ is (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₈R₉.

In certain embodiments R₁ is alkyl, aryl, alkylaryl, alkoxyaryl or heteroaryl substituted with halogen and R₂ is (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₈R₉.

In certain embodiments R₁ is aryl, alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₈R₉.

In certain embodiments R₁ is alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₁-C₆ alkyl)NR(C₁-C₆ alkyl)NR₈R₉.

In certain embodiments R₁ is alkylaryl substituted with halogen and R₂ is (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₈R₉.

In certain embodiments R₁ is (trifluoromethyl)phenyl and R₂ is (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₈R₉.

In certain embodiments R₂ is (C₀-C₃ alkyl)CH═NOR₇.

In certain embodiments R₁ is alkyl, aryl, alkylaryl, alkoxyaryl or heteroaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NOR₇.

In certain embodiments R₁ is aryl, alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NOR₇.

In certain embodiments R₁ is alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NOR₇.

In certain embodiments R₁ is alkylaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NOR₇.

In certain embodiments R₁ is (trifluoromethyl)phenyl and R₂ is (C₀-C₃ alkyl)CH═NOR₇.

In certain embodiments R₂ is (C₀-C₃ alkyl)CH═NNR₇R₈.

In certain embodiments R₁ is alkyl, aryl, alkylaryl, alkoxyaryl or heteroaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₇R₈.

In certain embodiments R₁ is aryl, alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₇R₈.

In certain embodiments R₁ is alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₇R₈.

In certain embodiments R₁ is alkylaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₇R₈.

In certain embodiments R₁ is (trifluoromethyl)phenyl and R₂ is (C₀-C₃ alkyl)CH═NNR₇R₈.

In certain embodiments R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)R₇.

In certain embodiments R₁ is alkyl, aryl, alkylaryl, alkoxyaryl or heteroaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)R₇.

In certain embodiments R₁ is aryl, alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)R₇.

In certain embodiments R₁ is alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)R₇.

In certain embodiments R₁ is alkylaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)R₇.

In certain embodiments R₁ is (trifluoromethyl)phenyl and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)R₇.

In certain embodiments R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)NR₇R₈.

In certain embodiments R₁ is alkyl, aryl, alkylaryl, alkoxyaryl or heteroaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)NR₇R₈.

In certain embodiments R₁ is aryl, alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)NR₇R₈.

In certain embodiments R₁ is alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)NR₇R₈.

In certain embodiments R₁ is alkylaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)NR₇R₈.

In certain embodiments R₁ is (trifluoromethyl)phenyl and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═O)NR₇R₈.

In certain embodiments R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═S)NR₇R₈.

In certain embodiments R₁ is alkyl, aryl, alkylaryl, alkoxyaryl or heteroaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═S)NR₇R₈.

In certain embodiments R₁ is aryl, alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═S)NR₇R₈.

In certain embodiments R₁ is alkylaryl or alkoxyaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═S)NR₇R₈.

In certain embodiments R₁ is alkylaryl substituted with halogen and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═S)NR₇R₈.

In certain embodiments R₁ is (trifluoromethyl)phenyl and R₂ is (C₀-C₃ alkyl)CH═NNR₃C(═S)NR₇R₈.

Exemplary compounds of the invention include:

ZDR018

ZDR019

ZDR022

ZDR022-HCI

ZDR024

ZDR025

ZDR026

ZDR027

ZDR028

ZDR029

ZDR030

ZDR031

ZDR033

ZDR035

ZDR041

ZDR043

ZDR045

ZDR046

ZDR061

ZDR062

ZDR063

ZDR064

ZDR065

ZDR066

ZDR067

ZDR068

ZDR069

ZDR070

ZDR071

ZDR072

ZDR073

ZDR074

ZDR075

ZDR076

ZDR077

ZDR078

ZDR079

ZDR080

ZDR081

ZDR082

ZDR084

ZDR085

ZDR086

ZDR087

ZDR088

ZDR089

ZDR090

ZDR091

ZDR092

ZDR093

ZDR094

ZDR095

ZDR096

ZDR097

ZDR098

ZDR099

ZDR100

ZDR101

ZDR102

ZDR103

ZDR106

ZDR107

ZDR108

ZDR109

ZDR110

ZDR111

ZDR112

ZDR113

ZDR114

ZDR115

ZDR116

ZDR117

ZDR118

ZDR119

ZDR120

ZDR121

ZDR122

ZDR123

ZDR124

ZDR125

ZDR126

ZDR127

ZDR129

ZDR130

ZDR131

ZDR132

ZDR133

ZDR135

ZDR136

ZDR137

ZDR138

ZDR143

ZDR145

ZDR148

ZDR153

ZDR154

ZDR155

ZDR160

ZDR162

ZDR163

ZDR164

ZDR167

ZDR170

ZDR171

ZDR176

ZDR180

ZDR181

ZDR184

ZDR185

ZDR187

ZDR188

ZDR190

ZDR191

ZDR192

ZDR193

ZDR194

ZDR195

ZDR196

ZDR201

ZDR202

ZDR203

ZDR204

ZDR205

ZDR209

ZDR210

ZDR211

ZDR224

ZDR257

ZDR258

ZDR259

ZDR261

ZDR262

ZDR263

ZDR265

ZDR266

ZDR267

ZDR268

ZDR269

ZDR270

ZDR305

ZDR306

ZDR307

ZDR308

ZDR309

ZDR310

ZDR311

ZDR312

ZDR313

ZDR314

ZDR315

ZDR316

ZDR317

ZDR318

ZDR319

ZDR320

ZDR321

ZDR322

ZDR323

ZDR324

ZDR326

ZDR327

ZDR328

ZDR330

ZDR331

ZDR332

ZDR333

ZDR335

ZDR336

ZDR337

ZDR338

ZDR339

ZDR340

ZDR401

ZDR402

ZDR403

ZDR404

ZDR405

ZDR406

ZDR407

ZDR408

ZDR409

ZDR500

ZDR501

ZDR502

ZDR503

ZDR504

ZDR505

ZDR506

Advantageously, e compounds described and claimed herein possess antibacterial activity against both Gram positive and Gram negative bacteria. Data to support these observations is presented in Tables 1 & 2 of Example 214, which follows. Specifically, exemplary compounds of the invention demonstrated both growth inhibitory and bactericidal activity against Streptococcus uberis, Staphylococcus aureus and Escherichia coli, as measured using MIC and MBC assays, respectively. In certain examples, the exemplary compounds advantageously demonstrate antibacterial activity in the absence of zinc (i.e. added exogenously to the assay medium).

Accordingly, in yet a further aspect of the invention of the invention there is provided a compound of Formula Ia:

wherein

R₁ is selected from the group comprising alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxyaryl, heterocyclyl, alkylheterocyclyl, alkoxyheterocyclyl, heteroaryl, alkylheteroaryl, alkoxyheteroaryl, C₁-C₆ alkyl(cycloalkyl), aralkyl, C₁-C₆ alkyl(alkylaryl), C₁-C₆ alkyl(alkoxyaryl), C₁-C₆ alkyl(heterocyclyl), C₁-C₆ alkyl(alkylheterocyclyl), C₁-C₆ alkyl(alkoxyheterocyclyl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(alkylheteroaryl), and C₁-C₆ alkyl(alkoxyheteroaryl), each of which is optionally substituted with one or more of halogen, OR₃, OCHO, OC(═O)R₃, SR₃, SCF₃, SC(═O)R₃, S(═O)R₃, S₂R₃, SO₃H, SO₂NR₃R₄, NR₃R₄, NR₃CHO, NR₃COR₄, NR₃CO₂R₄, NR₃SO₂R₄, NO₂, CN, CHO, COR₃, CO₂H, CO₂R₃, and CONR₃R₄;

R₂ is selected from the group comprising (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₇R₈, (C₁-C₆ alkyl)NR₇(C₀-C₆ alkyl)(pyridinyl), (C₁-C₆ alkyl)NR₇(C₀-C₆ alkyl)(hydroxyaryl), (C₁-C₆ alkyl)NR₇(C₁-C₆ hydroxyalkyl), (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)heterocyclyl, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₃C(═NR₃)NR₇R₈, (C₁-C₆ alkyl)NR₃C(═NR₃)NR₇R₈, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)C(═O)NR₇(C₁-C₆ alkyl), (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)C(═O)NR₇R₈, (C₀-C₃ alkyl)C═NNR₃C(═S)NR₇R₈, (C₀-C₃ alkyl)C═NNR₃C(═O)R₇ or (C₀-C₃ alkyl)C═NOR₃; each of which is optionally substituted with one or more of each of alkyl, halogen, OR₃, OCHO, OC(═O)R₃, SR₃, SC(═O)R₃, S(═O)R₃, S₂R₃, SO₃H, SO₂NR₃R₄, NR₃R₄, NR₃CHO, NR₃COR₄, NR₃CO₂R₄, NR₃C(═O)NR₄R₅, NR₃C(═S)NR₄R₅, NR₃C(═NR₄)NR₅R₆, NR₃C(═NNO₂)NR₄R₅, NR₃C(═NCN)NR₄R₅, NR₃C(═CHNO₂)NR₄R₅, NR₃C(═NR₄)R₅, NR₃S₂R₄, NO₂, CN, CHO, COR₃, CO₂H, CO₂R₃, CONR₃R₄, C(═O)NR₃OR₃, C(═O)NR₃NR₄R₅, C(═O)NR₃CN;

R₃, R₄, R₅ and R₆ are each selected from the group comprising hydrogen, alkyl, aryl and aralkyl; and

R₇, R₈ and R₉ are each selected from the group comprising hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxyaryl, heterocyclyl, alkylheterocyclyl, alkoxyheterocyclyl, heteroaryl, alkylheteroaryl, alkoxyheteroaryl, C₁-C₆ alkyl(cycloalkyl), aralkyl, C₁-C₆ alkyl(alkylaryl), C₁-C₆ alkyl(alkoxyaryl), C₁-C₆ alkyl(heterocyclyl), C₁-C₆ alkyl(alkylheterocyclyl), C₁-C₆ alkyl(alkoxyheterocyclyl), C₁-C₆ alkyl(heteroaryl), C₁-C₆ alkyl(alkylheteroaryl), C₁-C₆ alkyl(alkoxyheteroaryl), monosaccharide, disaccharide, each of which is optionally substituted with one or more of halogen, OR₃, OCHO, OC(═O)R₃, SR₃, SC(═O)R₃, S(═O)R₃, SO₂R₃, SO₃H, SO₂NR₃R₄, NR₃R₄, NR₃CHO, NR₃COR₄, NR₃CO₂R₄, NR₃C(═O)NR₄R₅, NR₃C(═S)NR₄R₅, NR₃C(═NR₄)NR₅R₆, NR₃C(═NNO₂)NR₄R₅, NR₃C(═NCN)NR₄R₅, NR₃C(═CHNO₂)NR₄R₅, NR₃C(═NR₄)R₅, NR₃S₂R₄, NO₂, CN, CHO, COR₃, CO₂H, CO₂R₃, CONR₃R₄, C(═O)NR₃OR₃, C(═O)NR₃NR₄R₅, C(═O)NR₃CN;

or a pharmaceutically acceptable salt or hydrate thereof.

In certain embodiments, the compound defined by Formula Ia is selected from ZDR030, ZDR035, ZDR046, ZDR090, ZDR102, ZDR111, ZDR112, ZDR113, ZDR114, ZDR115, ZDR116, ZDR117, ZDR119, ZDR120, ZDR121, ZDR122, ZDR124, ZDR125, ZDR143, ZDR167, ZDR170, ZDR171, ZDR187, ZDR261, ZDR262ZDR266, ZDR268 and ZDR269.

In another aspect the present invention provides a compound defined as ZDR022.HCl.

In another aspect the present invention provides a compound defined as ZDR090.

In another aspect the present invention provides a compound defined as ZDR091.

In another aspect the present invention provides a compound defined as ZDR092.

In another aspect the present invention provides a compound defined as ZDR095.

In another aspect the present invention provides a compound defined as ZDR102.

In another aspect the present invention provides a compound defined as ZDR111.

In another aspect the present invention provides a compound defined as ZDR112.

In another aspect the present invention provides a compound defined as ZDR114.

In another aspect the present invention provides a compound defined as ZDR115.

In another aspect the present invention provides a compound defined as ZDR116.

In another aspect the present invention provides a compound defined as ZDR117.

In another aspect the present invention provides a compound defined as ZDR119.

In another aspect the present invention provides a compound defined as ZDR120.

In another aspect the present invention provides a compound defined as ZDR121.

In another aspect the present invention provides a compound defined as ZDR122.

In another aspect the present invention provides a compound defined as ZDR124.

In another aspect the present invention provides a compound defined as ZDR125.

In another aspect the present invention provides a compound defined as ZDR127.

In another aspect the present invention provides a compound defined as ZDR143.

In another aspect the present invention provides a compound defined as ZDR167.

In another aspect the present invention provides a compound defined as ZDR170.

In another aspect the present invention provides a compound defined as ZDR171.

In another aspect the present invention provides a compound defined as ZDR187.

In another aspect the present invention provides a compound defined as ZDR224.

In another aspect the present invention provides a compound defined as ZDR261.

In another aspect the present invention provides a compound defined as ZDR269.

In another aspect the present invention provides a compound defined as ZDR335.

In yet another aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.

In certain embodiments the composition is a veterinary pharmaceutical composition.

In certain embodiments the composition further comprises an antibacterial compound selected from the group comprising chlorhexidine, iodine, lactic acid, cetrimide, BZK (benzylalkonium chloride), amoxicillin, erythromycin, cloxacillin, pirlimycin, cephapirin, hetacillin, penicillin, nicin and lacticin.

In certain embodiments the composition is formulated as a tablet, capsule or powder, or as a solution, suspension or dispersion for oral, injectable or sprayable administration.

In another aspect of the invention there is provided a method of treating or preventing a bacterial infection in an animal comprising administering to an animal a pharmaceutically effective amount of a compound of the invention.

In certain embodiments according to this aspect of the invention the compound is selected from ZDR022.HCl, ZDR090, ZDR091, ZDR092, ZDR095, ZDR102, ZDR111, ZDR112, ZDR114, ZDR115, ZDR116, ZDR117, ZDR119, ZDR120, ZDR121, ZDR122, ZDR124, ZDR125, ZDR127, ZDR143, ZDR167, ZDR170, ZDR171, ZDR187, ZDR224, ZDR261, ZDR269 and ZDR335.

In certain embodiments the bacterial infection is caused by one or more bacteria from the Enterobactericeae, Staphylococcaceae, and Streptococcaceae families. By way of non-limiting example, this includes Streptococcus uberis, Staphylococcus aureus, Staphylococcus agalactiae, and Escherichia coli.

In certain embodiments the bacterial infection is mastitis.

In certain embodiments the animal is a bovine cow.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a general mechanism of metal translocation by a compound of the invention.

DETAILED DESCRIPTION Definitions

The term “alkyl” means any saturated hydrocarbon radical and is intended to include both straight-chain and branched-chain alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, and 1-methyl-2-ethylpropyl. The term “C1-C6 alkyl” means any alkyl radical having up to 6 carbon atoms.

The term “alkenyl” means any hydrocarbon radical having at least one double bond, and is intended to include both straight- and branched-chain alkenyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, iso-propenyl, n-butenyl, sec-butenyl, n-pentenyl, 1,1-dimethylpropenyl, 1,2-dimethylpropenyl, 2,2-dimethylpropenyl, 1-ethylpropenyl, 2-ethylpropenyl, n-hexenyl, and 1-methyl-2-ethylpropenyl.

The term “alkynyl” means any hydrocarbon radical having at least one triple bond, and is intended to include both straight- and branched-chain alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, n-propynyl, n-butynyl, iso-butynyl, sec-butynyl, t-butynyl, n-pentynyl, 1,1-dimethylpropynyl, 2,2-dimethylpropynyl, 1-ethylpropynyl, 2-ethylpropynyl, n-hexynyl, and 1-methyl-2-ethylpropynyl.

The term “alkylene” means a diradical corresponding to an alkyl group. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

The term “cycloalkyl” means a saturated or partially saturated non-aromatic carbocyclic group, having preferably from 3 to 8 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term “heterocyclyl” means a cycloalkyl group where one or more of the ring carbon atoms is replaced with one or more heteroatoms, e.g. nitrogen, oxygen or sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, aziridinyl, thiiranyl, 1,2-dithietanyl, morpholinyl, furanyl, pyranyl, thiophenyl, isoxazolyl, furazanyl, tetrahydrofuranyl, thietanyl, piperidinyl, azetidinyl, oxiranyl, epoxide, and thiacyclohexyl.

The term “alkoxy” means an alkyl group singular bonded to an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and t-butoxy,

The term “aryl” means an aromatic radical. Examples include monocyclic groups as well as fused groups such as bicyclic groups and tricyclic groups. Examples include, but are not limited to, phenyl, indenyl, 1-naphthyl, 2-naphthyl, azulenyl, heptalenyl, biphenyl, indacenyl, acenaphthyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, cyclopentacyclooctenyl, and benzocyclooctenyl.

The term “heteroaryl” means a heterocyclic aromatic (heteroaromatic) radical. Examples include monocyclic groups as well as fused groups such as bicyclic groups and tricyclic groups. Examples include, but are not limited to, pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, imidazolyl, benzimidazolyl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, furyl, pyranyl, benzofuryl, isobenzofuryl, thienyl, thiazolyl, isothiazolyl, benzothiazolyl, oxazolyl, and isoxazolyl.

The term “aralkyl” means an aryl group which is attached to an alkylene moiety, where “aryl” and “alkylene” are as defined above. Examples include benzyl.

The term “alkylaryl” means an alkyl group which is attached to an aryl group, where “alkyl” and “aryl” are defined above. Examples include methylphenyl.

The term “alkoxyaryl” means an alkoxy group which is attached to an aryl group, where “alkoxy” and “aryl” are defined above. Examples include methoxyphenyl.

The term “alkylheteroaryl” means an alkyl group which is attached to heteroaryl group, where “alkyl” and “heteroaryl” are defined above. Examples include methylpyridinyl.

The term “alkoxyheteroaryl” means alkoxy group which is attached to heteroaryl group, where “alkoxy” and “heteroaryl” are defined above. Examples includes methoxypyridinyl.

The term “prodrug” as used herein refers to a drug substance that is inactive or weakly active in the intended pharmacological actions and is converted into the pharmacologically active or more active agent by metabolic or physico-chemical transformation.

The term “pharmaceutical composition” as used herein refers to a mixture of one or more of the compounds of formula (I), or pharmaceutically acceptable salts, or hydrates thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Non-limiting examples of such pharmaceutical carriers include liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carrier may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and colouring agents may be used. Other examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin, herein incorporated by reference.

The term “effective amount” means an amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” will vary depending on the disease to be treated, the compound to be administered, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, whether the treatment is monotherapy or combination therapy, the judgement of the attending clinician, and other factors.

The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

The term “pharmaceutically acceptable salt” as used herein refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use and is intended to include salts derived from inorganic or organic acids including, for example hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluroacetic, trichloroacetic, naphthalene-2 sulfonic and other acids. Pharmaceutically acceptable salt forms may also include forms wherein the ratio of molecules comprising the salt is not 1:1. For example, the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of formula (I).

Compounds of the Invention

The compounds of the invention are defined according to formula (I) above. The applicants have found that the compounds of the invention are effective inhibitors of several bacterial strains. As will be appreciated, there is an expectation that the compounds will be inhibitors of a larger group of bacteria.

The compounds are characterised as having a substituted sulfonamide group at the 8-position of the quinoline ring structure and a substituent at the 2-position. Without being bound by theory, it is considered that the pK_(a) of the sulfonamide hydrogen plays a role in the ability of the compound to act as an ionophore and therefore that an electron withdrawing group on the sulfonamide substituent is preferable. Examples of electron withdrawing groups include halogen, haloalkyl, haloalkoxy, alkyl carbonyl, alkyl ester, carboxylic acid, nitrile, and nitro.

The substituent at the 2-position may be chosen from a large variety of different types of groups. Some preferred groups are those that incorporate a nitrogen functionality. Again without being bound by theory, it is thought that those compounds having an amino group one carbon removed from the quinoline ring at the 2-position may beneficially interact, in combination with the quinoline nitrogen and the sulfonamide nitrogen, with a zinc cation.

Preparation of Compounds of the Invention

The compounds of the invention may be prepared by any known or standard synthetic procedures. Some compounds may be prepared according to scheme 1 from 8-amino-2-methylquinoline by reaction firstly with a substituted sulfonyl chloride, followed by oxidation of the 2-methyl group to an aldehyde (to give a 2-formyl derivative), and then reductive amination.

Alternatively, some compounds may be prepared according to scheme 2 from 8-amino-2-methylquinoline (which is first protected as a carbamate) via oxidation of the 2-methyl group to an aldehyde (to give a 2-formyl derivative), reductive amination (followed by deprotection) and then reaction with a substituted sulfonyl chloride.

Acyhydrazones and semicarbazones/thiosemicarbazones may be prepared from a common 2-formyl pre-cursor according to schemes 3 and 4, respectively.

Oximes and hydrazones may be prepared from a common 2-formyl pre-cursor according to schemes 5 and 6, respectively.

Aminomethyl derivatives (including amides, guanidines, nitro-guanidines and sulfonamides) may be prepared from a common 2-aminomethyl precursor (via an oxime, scheme 5) according to scheme 7.

Amino amide derivatives may be prepared from a common N-boc-protected amino acid precursor (via an N-hydroxysuccinimide ester) according to scheme 8.

Amide derivatives may be prepared from a common carboxylic acid precursor (itself accessed through the oxidation of a 2-formyl precursor, scheme 1) according to scheme 9.

Pharmaceutical Formulations and Administration

The compounds of the invention may be administered to a human or animal patient by a variety of mutes, including orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, intravenously, intra-muscularly, intra-dermally, subcutaneously or via an implanted reservoir, preferably intravenously. The amount of compound to be administered will vary widely according to the nature of the patient and the nature and extent of the disorder to be treated. Typically the dosage for an adult human will be in the range 50-4800 μg/m² or μg/kg. The specific dosage required for any particular patient will depend upon a variety of factors, including the patient's age, body weight, general health, sex, etc.

For oral administration, the compounds of the invention can be formulated into solid or liquid preparations, for example tablets, capsules, powders, solutions, suspensions and dispersions. Such preparations are well known in the art as are other oral dosage regimes not listed here. In the tablet form the compounds may be tableted with conventional tablet bases such as lactose, sucrose and corn starch, together with a binder, a disintegration agent and a lubricant. The binder may be, for example, corn starch or gelatin, the disintegrating agent may be potato starch or alginic acid, and the lubricant may be magnesium stearate. For oral administration in the form of capsules, diluents such as lactose and dried corn-starch may be employed. Other components such as colourings, sweeteners or flavourings may be added.

When aqueous suspensions are required for oral use, the active ingredient may be combined with carriers such as water and ethanol, and emulsifying agents, suspending agents and/or surfactants may be used. Colourings, sweeteners or flavourings may also be added.

The compounds may also be administered by injection in a physiologically acceptable diluent such as water or saline. The diluent may comprise one or more other ingredients such as ethanol, propylene glycol, an oil or a pharmaceutically acceptable surfactant. In one preferred embodiment, the compounds are administered by intravenous injection, where the diluent comprises an aqueous solution of sucrose, L-histidine and a pharmaceutically acceptable surfactant, e.g. Tween 20.

The compounds may also be administered topically, including as a spray particularly for some animal indications such as mastitis. Carriers for topical administration of the compounds include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Some teat spray formulations for treating mastitis may include glycerol and one or more surfactants in addition to other carriers. The compounds may be present as ingredients in lotions or creams, for topical administration to skin or mucous membranes. Such creams may contain the active compounds suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds may further be administered by means of sustained release systems. For example, they may be incorporated into a slowly dissolving tablet or capsule.

The compounds of the invention may also be administered in combination with other antimicrobial compounds such as chlorhexidine, iodine, lactic acid, cetrimide, BZK (benzylalkonium chloride), amoxicillin, erythromycin, cloxacillin, pirlimycin, cephapirin, hetacillin and penicillin, and bacteriocins such as nisin and lacticin. Such combinations may administered in any form including teat sprays for bovine cows and other animals.

Further, the compounds of the invention may be used alone or in combination with other active ingredients in external or internal teat seal formulations. Teat seals provide a physical barrier to prevent bacteria accessing the teat or udder of a cow. External teat seals provide a barrier across the entrance to the teat canal. The end of each teat is dipped in a teat seal formulation after milking has ended. The seal then dries to provide a film that prevents entry of bacteria to the teat canal. Internal teat seals are typically pastes that are infused into each quarter of a cow's udder at the start of the drying off period. The paste forms an internal physical barrier to bacteria entering the teat canal. Many internal teat seal formulations comprise bismuth sub-nitrate and a heavy metal salt such as barium sulfate, often formulated as gels which solidify after administration. One example is TEATSEAL™.

Proposed Mechanism of Action

The applicant does not wish to be bound by theory, but proposes that mechanism of killing of bacteria by a compound of the invention is three-fold. Firstly, the compound is able to translocate zinc into the bacterial cytoplasm (inside the bacterial cell). Accumulation of zinc overcomes the zinc homeostatic apparatus of the bacterial cells, leading to cell death through zinc toxicity. Secondly, the compounds exert their effect in a bacterial-specific manner as an ionophore by depolarising the proton motive force (pmf). Finally, zinc-chelation by the compound in the external media limits the amount of bio-available zinc, leading to extracellular zinc starvation of the bacterium.

It is thought that zinc ionophores translocate protons (H⁺) in exchange for metal ions (M⁺) across cell membranes (FIG. 1 ). When the external pH is higher than the acid dissociation constant (pK_(a)) of the ionophore, the ionophore is predominately deprotonated, and able to form an ionophore-metal complex (MI). When the pH is lower than the pK_(a) of the ionophore, the metal ion is released as the ionophore becomes protonated (HI). Depending on the properties of the ionophore, they can accumulate in the membrane as shown in FIG. 1 , or are able to diffuse through the membrane into extracellular or intracellular spaces.

Summary of Biological Data

All quinoline sulfonamide compounds synthesised to date have been examined for their inhibitory properties against the three-major mastitis-causing microorganisms in New Zealand, these being S. uberis, S. aureus, or E. coli. Minimum inhibitory concentrations were determined, initially in the absence of any additional zinc (above that contained in the media), and with an additional 50 μM zinc (zinc sulfate). MIC data is summarised in Table 1. In addition to the inhibitory activity of the quinoline sulfonamide compounds, specific compounds were assessed for their ability to kill mastitis-causing microorganisms as shown in Table 2. It is anticipated that the bacterial strains potentially inhibited by compounds of the invention include other members of the Enterobactericeae, Staphylococcaceae, and Streptococcaceae families.

Any reference to prior art documents in this specification is not to be considered an admission that such prior art is widely known or forms part of the common general knowledge in the field.

As used in this specification, the words “comprises”, “comprising”, and similar words, are not to be interpreted in an exclusive or exhaustive sense. In other words, they are intended to mean “including, but not limited to”.

The invention is further described with reference to the following examples. It will be appreciated that the invention as claimed is not intended to be limited in any way by these examples.

EXAMPLES Example 1: N-(2-Methylquinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR018)

A solution of 8-amino-2-methylquinoline (10.0 g, 63.2 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (17.0 g, 69.5 mmol) and triethylamine (10.5 mL, 75.8 mmol) in dichloromethane (100 mL) was stirred at room temperature for 18 h. The mixture was then diluted with water (100 mL), the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7) and the separated aqueous layer further extracted with dichloromethane (2×50 mL). The combined organic layers were further washed with aqueous phosphate buffer solution (0.5 M, pH 7) (50 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford compound (ZDR018) as a pale grey solid (22.40 g), which was used without further purification. ¹H NMR (300 MHz, CDCl₃) δ 2.68 (3H, s), 7.28 (1H, d, J=8.4 Hz), 7.37 (1H, t, J=7.4 Hz), 7.45 (1H, dd, J=7.4 and 1.4 Hz), 7.61 (2H, d, J=8.2 Hz), 7.79 (1H, dd, J=7.4 and 1.4 Hz), 7.98 (1H, d, J=8.4 Hz), 8.01 (2H, d, J=8.2 Hz); ESI-MS: m/z calcd for C₁₇H₁₃F₃N₂O₂S: 366.1; found [M+H]⁺: 367.1.

Example 2: N-(2-Formylquinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR019)

A solution of compound (ZDR018) (22.40 g) and selenium dioxide (7.45 g, 67.2 mmol) In 1,4-dioxane (400 mL) was heated at 85° C. for 10 h. The mixture was allowed to cool to room temperature then filtered through Celite®, and the filtrate concentrated in vacuo. Purification by flash chromatography (petroleum ether/ethyl acetate, 4:1→2:1→1:1) afforded compound (ZDR019) as an off-white solid (18.50 g, 48.6 mmol, 77% over 2 steps). ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.63 (2H, m), 7.68 (2H, d, J=8.4 Hz), 7.93-7.96 (1H, m), 8.06 (1H, d, J=8.4 Hz), 8.09 (2H, d, J=8.4 Hz), 8.31 (1H, d, J=8.4 Hz), 9.21 (1H, br s), 10.20 (1H, s); ESI-MS: m/z calcd for C₁₇H₁₁F₃N₂O₃S: 380.0; found [M+H]⁺: 381.1.

Example 3: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)-benzenesulfonamide—Compound (ZDR022)

A solution of compound (ZDR019) (3.0 g, 7.88 mmol), dimethylamine hydrochloride (1.92 g, 23.6 mmol), sodium triacetoxyborohydride (3.32 g, 15.7 mmol) and N,N-diisopropylethylamine (4.8 mL, 27.5 mmol) in 1,2-dichloroethane (150 mL) was stirred at room temperature for 18 h. The reaction was quenched through the addition of water (100 mL) and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The mixture was then diluted with dichloromethane (100 mL) and the separated aqueous layer further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with aqueous phosphate buffer solution (0.5 M, pH 7) (100 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1→7:1) afforded compound (ZDR022) as a white solid (2.40 g, 5.86 mmol, 74%). ¹H NMR (300 MHz, CDCl₃) δ 2.32 (6H, s), 3.77 (2H, s), 7.40-7.48 (2H, m), 7.52 (1H, d, J=8.4 Hz), 7.57 (2H, d, J=8.3 Hz), 7.86 (1H, dd, J=7.3 and 1.6 Hz), 8.00 (2H, d, J=8.3 Hz), 8.07 (1H, d, 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 45.3 (CH₃), 65.5 (CH₂), 116.7 (CH), 122.1 (CH), 122.9 (CH), 123.2 (C, q, J=273 Hz), 126.0 (CH, q, J=3.6 Hz), 126.6 (CH), 127.4 (C), 127.7 (CH), 133.2 (C), 134.4 (C, q, J=33 Hz), 137.0 (CH), 138.2 (C), 143.2 (C), 157.8 (C). ¹H NMR (400 MHz, d₆-DMSO) δ 2.14 (6H, s), 3.59 (2H, s), 7.50 (1H, t, J=7.8 Hz), 7.57 (1H, d, J=8.5 Hz), 7.67-7.71 (2H, m), 7.80 (2H, d, J=8.2 Hz), 8.02 (2H, d, J=8.2 Hz), 8.25 (1H, d, J=8.5 Hz); ¹³C NMR (100 MHz, d₆-DMSO) δ 45.1 (CH₃), 65.1 (CH₂), 120.2 (CH), 121.5 (CH), 123.2 (C, q, J=273 Hz), 124.1 (CH), 126.0 (CH), 127.2 (C), 127.7 (CH), 132.3 (C, q, J=32 Hz), 132.9 (C), 136.6 (CH), 139.0 (C), 143.9 (C), 159.2 (C); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₂S: 409.1; found [M+H]⁺: 410.2.

Example 4: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)-benzenesulfonamide HCl—Compound (ZDR022 Hydrochloride)

To a solution of compound (ZDR022) (1.00 g, 2.44 mmol) in 1,4-dioxane (10 mL) was added aqueous hydrochloric acid (20 mL, 0.1 M), and the mixture lyophilized to dryness to afford compound (ZDR022 HCl) as a white solid (1.08 g, 2.44 mmol, quant.). ¹H NMR (400 MHz, d₆-DMSO) δ 2.83 (6H, s), 4.70 (2H, s), 7.56-7.61 (2H, m), 7.73 (1H, dd, J=8.4 and 1.0 Hz), 7.85-7.89 (3H, m), 8.13 (2H, d, J=8.2 Hz), 8.43 (1H, d, J=8.4 Hz), 10.82 (1H, s), 11.16 (1H, s); ¹³C NMR (100 MHz, d₆-DMSO) δ 42.7 (CH₃), 60.0 (CH₂), 118.8 (CH), 121.3 (CH), 123.2 (C, q, J=273 Hz), 123.5 (CH), 126.3 (CH, q, J=3.5 Hz), 127.2 (CH), 127.4 (C), 127.8 (CH), 132.5 (C, q, J=32 Hz), 133.2 (C), 138.0 (CH), 143.5 (C), 150.8 (C); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₂S: 409.1; found [M+H]⁺: 410.1.

Example 5: N-(2-((Methylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)-benzenesulfonamide—Compound (ZDR024)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), methylamine (72 mg, 0.78 mmol, 33 wt. % In absolute ethanol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR024) as a pale yellow solid (65 mg, 0.16 mmol, 62%). ¹H NMR (300 MHz, d₆-DMSO) δ 2.54 (3H, s), 4.29 (2H, s), 7.40-7.58 (5H, m), 7.67 (1H, d, J=7.3 Hz), 7.84 (2H, J=8.1 Hz), 8.25 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₆F₃N₃O₂S: 395.1; found [M+H]⁺: 396.1.

Example 6: N-(2-((Ethylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)-benzenesulfonamide—Compound (ZDR025)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), ethylamine (51 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR025) as a pale yellow solid (71 mg, 0.17 mmol, 65%). ¹H NMR (300 MHz, d₆-DMSO) δ 1.24 (3H, t, J=7.2 Hz), 2.89 (2H, q, J=7.2 Hz), 4.37 (2H, s), 7.51 (1H, t, J=7.9 Hz), 7.56 (1H, d, J=8.4 Hz), 7.65 (1H, d, J=7.9 Hz), 7.76-7.81 (3H, m), 8.02 (2H, d, J=8.1 Hz), 8.34 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₂S: 409.1; found [M+H]⁺: 410.1.

Example 7: N-(2-((Propylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)-benzenesulfonamide—Compound (ZDR026)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), n-propylamine (64 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR026) as a pale yellow solid (79 mg, 0.19 mmol, 73%). ¹H NMR (300 MHz, d₆-DMSO) δ 0.89 (3H, t, J=7.2 Hz), 1.55-1.62 (2H, m), 2.67 (2H, t, J=7.2 Hz), 4.17 (2H, s), 7.42-7.70 (6H, m), 7.94 (2H, d, J=8.1 Hz), 8.25 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₀F₃N₃O₂S: 423.1; found [M+H]⁺: 424.1.

Example 8: N-(2-((Isopropylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)-benzenesulfonamide—Compound (ZDR027)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), isopropylamine (64 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR027) as a pale yellow solid (67 mg, 0.16 mmol, 62%). ¹H NMR (300 MHz, d₆-DMSO) δ 1.11 (6H, d, J=6.3 Hz), 2.89-2.94 (1H, m), 4.10 (2H, s), 7.47 (1H, t, J=7.8 Hz), 7.55 (1H, d, J=8.4 Hz), 7.62 (1H, d, J=7.8 Hz), 7.70 (1H, dd, J=7.8 and 1.2 Hz), 7.74 (2H, d, J=8.2 Hz), 7.97 (2H, d, J=8.2 Hz), 8.26 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₀F₃N₃O₂S: 423.1; found [M+H]⁺: 424.1.

Example 9: N-(2-((Diethylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)-benzenesulfonamide—Compound (ZDR028)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), diethylamine (81 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR028) as a pale yellow solid (89 mg, 0.20 mmol, 77%). ¹H NMR (300 MHz, d₆-DMSO) δ 0.97 (6H, t, J=7.1 Hz), 2.48-2.51 (4H, m), 3.74 (2H, s), 7.51 (1H, t, J=7.7 Hz), 7.63 (1H, d, J=8.5 Hz), 7.69-7.71 (2H, m), 7.82 (2H, d, J=8.3 Hz), 8.01 (2H, d, J=8.3 Hz), 8.27 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₂₁H₂₂F₃N₃O₂S: 437.1; found [M+H]⁺: 438.1.

Example 10: N-(2-((Morpholin-4-yl)methyl)quinolin-8-yl)-4-(trifluoromethyl)-benzenesulfonamide—Compound (ZDR029)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), morpholine (68 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 30:1) afforded compound (ZDR029) as a white solid (82 mg, 0.18 mmol, 69%). ¹H NMR (300 MHz, CDCl₃) δ 2.47-2.50 (4H, m), 3.71-3.75 (4H, m), 3.76 (2H, s), 7.40-7.51 (2H, m), 7.59 (2H, d, J=8.2 Hz), 7.64 (1H, d, J=8.4 Hz), 7.83 (1H, dd, J=7.4 and 1.5 Hz), 8.00 (2H, d, J=8.2 Hz), 8.07 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₁H₂₀F₃N₃O₃S: 451.1; found [M+H]⁺: 452.0.

Example 11: N-(2-(((2-(Dimethylamino)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR030)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), N,N-dimethylethylenediamine (86 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1) afforded compound (ZDR030) as a pale brown solid (61 mg, 0.13 mmol, 50%). ¹H NMR (300 MHz, CDCl₃) δ 2.41 (6H, s), 2.76 (2H, t, J=5.8 Hz), 2.88 (2H, t, J=5.8 Hz), 4.12 (2H, s), 7.32-7.44 (3H, m), 7.57 (2H, d, J=8.2 Hz), 7.71-7.74 (1H, m), 7.98-8.04 (3H, m); ESI-MS: m/z calcd for C₂₁H₂₃F₃N₄O₂S: 452.1; found [M+H]⁺: 453.0.

Example 12: N-(2-(((2-Hydroxyethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR031)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), ethanolamine (47 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1) afforded compound (ZDR031) as a pale yellow solid (64 mg, 0.15 mmol, 58%). ¹H NMR (300 MHz, d₆-DMSO) δ 2.82 (2H, t, J=5.6 Hz), 3.64 (2H, t, J=5.6 Hz), 4.20 (2H, s), 7.40-7.68 (6H, m), 7.90 (2H, d, J=8.2 Hz), 8.23 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₃S: 425.1; found [M+H]⁺: 426.0.

Example 13: N-(2-((Piperidin-1-yl)methyl)quinolin-8-yl)-4-(trifluoromethyl)-benzenesulfonamide—Compound (ZDR033)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), piperidine (77 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1) afforded compound (ZDR033) as a white solid (88 mg, 0.19 mmol, 73%). ¹H NMR (300 MHz, CDCl₃) δ 1.46-1.54 (2H, m), 1.59-1.69 (4H, m), 2.44-2.52 (4H, m), 3.76 (2H, s), 7.49-7.50 (2H, m), 7.58-7.63 (3H, m), 7.83 (1H, dd, J=7.3 and 1.4 Hz), 8.01 (2H, d, J=8.2 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₂H₂₂F₃N₃O₂S: 449.1; found [M+H]⁺: 450.1.

Example 14: N-(2-((((Pyridin-2-yl)methyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR035)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-(aminomethyl)pyridine (81 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (petroleum ether/ethyl acetate, 1:1) afforded compound (ZDR035) as a pale yellow solid (85 mg, 0.18 mmol, 69%). ¹H NMR (300 MHz, CDCl₃) δ 3.95 (2H, s), 4.11 (2H, s), 7.20-7.26 (1H, m), 7.31 (1H, d, J=7.5 Hz), 7.40-7.51 (3H, m), 7.54 (2H, d, J=8.2 Hz), 7.65-7.70 (1H, m), 7.86 (1H, dd, J=7.5 and 1.4 Hz), 7.97 (2H, d, J=8.2 Hz), 8.05 (1H, d, J=8.4 Hz), 8.71-8.51 (1H, m); ESI-MS: m/z calcd for C₂₃H₁₉F₃N₄O₂S: 472.1; found [M+H]⁺: 473.0.

Example 15: N,N′-(((Ethane-1,2-diylbis(methylazanediyl))bis(methylene))-bis(quinoline-2,8-diyl))bis(4-(trifluoromethyl)benzenesulfonamide)—Compound (ZDR036)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), N,N′-dimethylethylenediamine (14 μL, 0.13 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR036) as a pale yellow solid (40 mg, 0.05 mmol, 38%). ¹H NMR (300 MHz, CDCl₃) δ 2.25 (2H, d, J=10.5 Hz), 2.31 (6H, s), 2.80 (2H, d, J=10.5 Hz), 3.83 (2H, d, J=15.4 Hz), 4.93 (2H, d, J=15.4 Hz), 7.14-7.30 (10H, m), 7.41 (2H, d, J=8.4 Hz), 7.69 (4H, d, J=8.3 Hz), 8.27 (2H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₃H₃₄F₆N₆O₄S₂: 816.2; found [M+H]⁺: 817.1.

Example 16: N,N′-(((Methylazanediyl)bis(methylene))bis(quinoline-2,8-diyl))bis(4-(trifluoromethyl)benzenesulfonamide)—Compound (ZDR037)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), methylamine (12 mg, 0.13 mmol, 33 wt. % in absolute ethanol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 30:1) afforded compound (ZDR037) as a pale yellow solid (45 mg, 0.06 mmol, 46%). ¹H NMR (400 MHz, CDCl₃) δ 2.25 (3H, s), 3.87 (4H, s), 7.43 (2H, t, J=7.8 Hz), 7.49 (2H, dd, J=7.8 and 1.4 Hz), 7.55 (4H, d, J=8.3 Hz), 7.67 (2H, d, J=8.3 Hz), 7.82 (2H, dd, J=7.8 and 1.4 Hz), 7.99 (4H, d, J=8.3 Hz), 8.10 (2H, d, J=8.3 Hz); ESI-MS: m/z calcd for C₃₅H₂₇F₆N₅O₄S₂: 759.1; found [M+H]⁺: 760.1.

Example 17: N-(2-(((tert-Butoxycarbonylmethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR041)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), glycine tert-butyl ester hydrochloride (132 mg, 0.78 mmol), triethylamine (109 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 30:1) afforded compound (ZDR041) as a pale yellow solid (94 mg, 0.19 mmol, 73%). ¹H NMR (300 MHz, CDCl₃) δ 1.49 (9H, s), 3.38 (2H, s), 4.06 (2H, s), 7.41-7.50 (3H, m), 7.61 (2H, d, J=8.2 Hz), 7.83 (1H, dd, J=7.4 and 1.5 Hz), 7.01-8.07 (3H, m); ESI-MS: m/z calcd for C₂₃H₂₄F₃N₃O₄S: 495.1; found [M+H]⁺: 496.0.

Example 18: N-(2-(((Carboxymethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide trifluoroacetate—Compound (ZDR043)

A solution of compound (ZDR041) (50 mg, 0.10 mmol) in trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) was stirred at room temperature for 36 h. The solvent was removed in vacuo to afford compound (ZDR043) as a pale brown solid (53 mg, 0.10 mmol, quant.), which was used without further purification. ¹H NMR (300 MHz, d₆-DMSO) δ 4.01 (2H, s), 4.62 (2H, s), 7.55-7.60 (1H, m), 7.58 (1H, d, J=8.4 Hz), 7.72 (1H, dd, J=7.9 and 1.0 Hz), 7.85 (2H, d, J=8.2 Hz), 7.89 (1H, dd, J=7.9 and 1.0 Hz), 8.07 (2H, d, J=8.2 Hz), 8.42 (1H, d, J=8.4 Hz), 9.78 (2H, br s), 10.62 (1H, s); ESI-MS: m/z calcd for C₁₉H₁₆F₃N₃O₄S: 439.1; found [M+H]⁺: 440.0.

Example 19: (E)-N-(2-((2-Benzoylhydrazono)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR045)

A solution of compound (ZDR019) (0.25 mg, 0.65 mmol) and benzhydrazide (89 mg, 0.65 mmol) in aqueous ethanol (20 mL, 90% v/v) was stirred at 70° C. for 18 h. The mixture was allowed to cool to room temperature and the precipitated product was collected by filtration and washed with ice-cold ethanol (2×2 mL) to afford compound (ZDR045) as a white solid (250 mg, 0.50 mmol, 77%), which was used without further purification. ¹H NMR (300 MHz, d₆-DMSO) δ 7.55-7.64 (4H, m), 7.71 (1H, dd, J=7.8 and 1.1 Hz), 7.78 (1H, d, J=7.8 Hz), 7.84 (2H, d, J=8.3 Hz), 7.90-8.10 (5H, m), 8.37 (1H, d, J=8.5 Hz), 8.51 (1H, s), 10.40 (1H, s), 12.23 (1H, s); ESI-MS: m/z calcd for C₂₄H₁₇F₃N₄O₃S: 498.1; found [M+H]⁺: 499.0.

Example 20: (E)-2-((8-((4-(Trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methylene)hydrazine-1-carbothioamide—Compound (ZDR046)

A similar procedure to that described for the preparation of compound (ZDR045) was followed using compound (ZDR019) (0.25 mg, 0.65 mmol) and thiosemicarbazide (59 mg, 0.65 mmol) in ethanol (30 mL) to afford compound (ZDR046) as a white solid (210 mg, 0.46 mmol, 71%), which was used without further purification. ¹H NMR (300 MHz, d₆-DMSO) δ 7.52 (1H, t, J=7.8 Hz), 7.64 (1H, d, J=7.8 Hz), 7.71 (1H, d, J=7.8 Hz), 7.84 (2H, d, J=8.3 Hz), 8.03-8.10 (3H, m), 8.39-8.43 (2H, m), 10.43 (1H, s), 11.87 (1H, s); ESI-MS: m/z calcd for C₁₈H₁₄F₃N₅O₂S₂: 453.1; found [M+H]⁺: 454.0.

Example 21: tert-Butyl (2-methylquinolin-8-yl)carbamate—Compound (ZDR056)

A solution of 8-amino-2-methylquinoline (11.66 g, 73.6 mmol) and di-tert-butyl dicarbonate (32.2 g, 147.3 mmol) in 1,4-dioxane (200 mL) was heated at 90° C. for 48 h, and the solvent then removed in vacuo. Purification by flash chromatography (petroleum ether/ethyl acetate, 100:1→20:1), followed by crystallisation from petroleum ether/ethanol (10:1 v/v), afforded compound (ZDR056) as a yellow solid (14.62 g, 56.6 mmol, 76%). ¹H NMR (400 MHz, CDCl₃) δ 1.59 (9H, s), 2.74 (3H, s), 7.29 (1H, d, J=8.4 Hz), 7.35-7.38 (1H, m), 7.43 (1H, t, J=7.5 Hz), 8.00 (1H, d, J=8.4 Hz), 8.37 (1H, d, J=7.5 Hz), 9.05 (1H, brs).

Example 22: tert-Butyl (2-formylquinolin-8-yl)carbamate—Compound (ZDR057)

A solution of compound (ZDR056) (4.34 g, 16.8 mmol) and selenium dioxide (3.36 g, 30.2 mmol) in 1,4-dioxane (200 mL) was heated at 85° C. for 18 h. The mixture was then filtered through a pad of Celite® and the solvent removed in vacuo. Purification by flash chromatography (dichloromethane) afforded compound (ZDR057) as a yellow solid (3.43 g, 12.5 mmol, 74%). ¹H NMR (400 MHz, CDCl₃) δ 1.61 (9H, s), 7.50 (1H, dd, J=7.9 and 1.7 Hz), 7.66 (1H, t, J=7.9 Hz), 8.05 (1H, d, J=8.4 Hz), 8.29 (1H, d, J=8.4 Hz), 8.52 (1H, d, J=7.9 Hz), 8.99 (1H, brs), 10.25 (1H, s).

Example 23: tert-Butyl (2-((dimethylamino)methyl)quinolin-8-yl)carbamate—Compound (ZDR058)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR057) (7.0 g, 25.7 mmol), dimethylamine hydrochloride (4.19 g, 51.4 mmol), sodium triacetoxyborohydride (10.90 g, 51.4 mmol) and N,N-diisopropylethylamine (9.0 mL, 51.4 mmol) in 1,2-dichloroethane (350 mL). Purification by flash chromatography (dichloromethane/methanol, 10:1) afforded compound (ZDR058) as a yellow oil (6.70 g, 22.2 mmol, 86%). ¹H NMR (400 MHz, CDCl₃) δ 1.59 (9H, s), 2.49 (6H, s), 4.00 (2H, s), 7.41 (1H, dd, J=7.8 and 1.5 Hz), 7.49 (1H, t, J=7.8 Hz), 7.66 (1H, d, J=8.4 Hz), 8.14 (1H, d, J=8.4 Hz), 8.41 (1H, d, J=7.8 Hz), 9.03 (1H, brs).

Example 24: 2-((Dimethylamino)methyl)quinolin-8-amine—Compound (ZDR059)

A solution of compound (ZDR058) (1.50 g, 4.98 mmol) in trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) was stirred at room temperature for 3 h, and the solvent then removed in vacuo. The resulting residue was taken up in dichloromethane (100 mL) and washed with aqueous sodium bicarbonate (2×100 mL), and the separated aqueous layers then further extracted with dichloromethane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 50:1→10:1) afforded compound (ZDR059) as a yellow solid (477 mg, 2.36 mmol, 47%). ¹H NMR (300 MHz, d₄-MeOH) δ 2.31 (6H, s), 3.73 (2H, s), 6.94 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=7.8 Hz), 7.26 (1H, t, J=7.8 Hz), 7.36 (1H, d, J=8.4 Hz), 8.03 (1H, d, J=8.4 Hz).

Example 25: N-(2-((Dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR061)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), benzenesulfonyl chloride (62 μL, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR061) as a tan solid (104 mg, 0.30 mmol, 68%). ¹H NMR (300 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 7.29-7.45 (5H, m), 7.57 (1H, d, J=8.4 Hz), 7.80 (1H, dd, J=7.0 and 1.8 Hz), 7.86-7.90 (2H, m), 8.04 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₉N₃O₂S: 341.1; found [M+H]⁺: 342.1.

Example 26: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-methylbenzenesulfonamide—Compound (ZDR062)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-toluenesulfonyl chloride (93 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR062) as a tan solid (101 mg, 0.28 mmol, 63%). ¹H NMR (300 MHz, CDCl₃) δ 2.26 (3H, s), 2.29 (6H, s), 3.70 (2H, s), 7.11 (2H, d, J=8.0 Hz), 7.35-7.45 (2H, m), 7.57 (1H, d, J=8.4 Hz), 7.74-7.80 (3H, m), 8.04 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₂₁N₃O₂S: 355.1; found [M+H]⁺:356.1.

Example 27: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-methoxybenzenesulfonamide—Compound (ZDR063)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-methoxybenzenesulfonyl chloride (101 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR063) as an off-white solid (77 mg, 0.20 mmol, 45%). ¹H NMR (300 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 3.72 (3H, s), 6.76 (2H, d, J=8.9 Hz), 7.35-7.44 (2H, m), 7.57 (1H, d, J=8.4 Hz), 7.75-7.83 (3H, m), 8.03 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₂₁N₃O₃S: 371.1; found [M+H]⁺: 372.1.

Example 28: 4-Chloro-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR064)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-chlorobenzenesulfonyl chloride (103 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR064) as a beige solid (96 mg, 0.25 mmol, 56%). ¹H NMR (300 MHz, CDCl₃) δ 2.30 (6H, s), 3.71 (2H, s), 7.27-7.31 (2H, m), 7.39-7.50 (2H, m), 7.60 (1H, d, J=8.4 Hz), 7.79-7.83 (3H, m), 8.08 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₈ClN₃O₂S: 375.1; found [M+H]⁺: 376.1.

Example 29: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-fluorobenzenesulfonamide—Compound (ZDR065)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-fluorobenzenesulfonyl chloride (95 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR065) as a tan solid (100 mg, 0.27 mmol, 61%). ¹H NMR (300 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 6.94-7.00 (2H, m), 7.37-7.47 (2H, m), 7.57 (1H, d, J=8.4 Hz), 7.80 (1H, dd, J=7.2 and 1.5 Hz), 7.86-7.91 (2H, m), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₈FN₃O₂S: 359.1; found [M+H]⁺: 360.1.

Example 30: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-(trifluoromethoxy)benzenesulfonamide—Compound (ZDR066)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-(trifluoromethoxy)benzenesulfonyl chloride (127 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR066) as a beige solid (96 mg, 0.22 mmol, 50%). ¹H NMR (300 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 7.10-7.14 (2H, m), 7.38-7.49 (2H, m), 7.56 (1H, d, J=8.4 Hz), 7.82 (1H, dd, J=7.3 and 1.5 Hz), 7.89-7.94 (2H, m), 8.06 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₃S: 425.1; found [M+H]⁺: 426.1.

Example 31: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-nitrobenzenesulfonamide—Compound (ZDR067)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-nitrobenzenesulfonyl chloride (108 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR067) as an orange solid (80 mg, 0.20 mmol, 45%). ¹H NMR (300 MHz, CDCl₃) δ 2.30 (6H, s), 3.72 (2H, s), 7.41-7.53 (2H, m), 7.57 (1H, d, J=8.4 Hz), 7.86 (1H, dd, J=7.4 and 1.4 Hz), 8.05-8.09 (3H, m), 8.13-8.17 (2H, m); ESI-MS: m/z calcd for C₁₈H₁₈N₄O₄S: 386.1; found [M+H]⁺: 387.1.

Example 32: 4-Cyano-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR068)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-cyanobenzenesulfonyl chloride (98 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR068) as a pale orange solid (107 mg, 0.29 mmol, 65%). ¹H NMR (300 MHz, CDCl₃) δ 2.30 (6H, s), 3.71 (2H, s), 7.39-7.62 (5H, m), 7.82 (1H, dd, J=7.4 and 1.4 Hz), 7.97-8.01 (2H, m), 8.07 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₁₈N₄O₂S: 366.1; found [M+H]⁺: 367.1.

Example 33: Methyl 4-(N-(2-((dimethylamino)methyl)quinolin-8-yl)sulfamoyl)benzoate—Compound (ZDR069)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-chlorosulfonylbenzoic acid methyl ester (114 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR069) as a beige solid (88 mg, 0.22 mmol, 50%). ¹H NMR (300 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 3.85 (3H, s), 7.37-7.47 (2H, m), 7.56 (1H, d, J=8.4 Hz), 7.82 (1H, dd, J=7.4 and 1.5 Hz), 7.91-7.98 (4H, m), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₁N₃O₄S: 399.1; found [M+H]⁺: 400.1.

Example 34: 4-Acetyl-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR070)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-acetylbenzenesulfonyl chloride (107 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR070) as a tan solid (66 mg, 0.17 mmol, 38%). ¹H NMR (300 MHz, CDCl₃) δ 2.28 (6H, s), 2.51 (3H, s), 3.70 (2H, s), 7.37-7.47 (2H, m), 7.56 (1H, d, J=8.4 Hz), 7.80-7.87 (3H, m), 7.94-7.99 (2H, m), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₁N₃O₃S: 383.1; found [M+H]⁺: 384.1.

Example 35: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-(methylsulfonyl)benzenesulfonamide—Compound (ZDR071)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-(methylsulfonyl)benzenesulfonyl chloride (124 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR071) as an off-white solid (83 mg, 0.19 mmol, 43%). ¹H NMR (300 MHz, CDCl₃) δ 2.29 (6H, s), 2.97 (3H, s), 3.70 (2H, s), 7.39-7.51 (2H, m), 7.58 (1H, d, J=8.4 Hz), 7.83 (1H, dd, J=7.4 and 1.5 Hz), 7.86-7.91 (2H, m), 8.06-8.09 (3H, m); ESI-MS: m/z calcd for C₁₉H₂₁N₃O₄S₂: 419.1; found [M+H]⁺: 420.1.

Example 36: N-(4-(N-(2-((Dimethylamino)methyl)quinolin-8-yl)sulfamoyl)phenyl)acetamide—Compound (ZDR072)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-acetamidobenzenesulfonyl chloride (114 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR072) as a pale yellow solid (60 mg, 0.15 mmol, 34%). ¹H NMR (300 MHz, CDCl₃) δ 2.10 (3H, s), 2.28 (6H, s), 3.70 (2H, s), 7.34-7.48 (41, m), 7.56 (1H, d, J=8.4 Hz), 7.73-7.80 (3H, m), 8.04 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₂N₄O₃S: 398.1; found [M+H]⁺: 399.1.

Example 37: 4-(N-(2-((Dimethylamino)methyl)quinolin-8-yl)sulfamoyl)benzamide—Compound (ZDR073)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-(chlorosulfonyl)benzamide (107 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR073) as a beige solid (70 mg, 0.18 mmol, 40%). ¹H NMR (300 MHz, CDCl₃) δ 2.30 (6H, s), 3.72 (2H, s), 7.37-7.48 (2H, m), 7.56 (1H, d, J=8.4 Hz), 7.70-7.74 (2H, m), 7.81 (1H, dd, J=7.4 and 1.4 Hz), 7.91-7.95 (2H, m), 8.06 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₂₀N₄O₃S: 384.1; found [M+H]⁺: 385.1.

Example 38: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3-(trifluoromethyl)benzenesulfonamide—Compound (ZDR074)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.49 mmol), 3-(trifluoromethyl)benzenesulfonyl chloride (87 μL, 0.54 mmol) and triethylamine (76 μL, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR074) as a pale orange solid (97 mg, 0.23 mmol, 46%). ¹H NMR (300 MHZ, CDCl₃) δ 2.27 (6H, s), 3.68 (2H, s), 7.40-7.50 (3H, m), 7.55-7.64 (2H, m), 7.84 (1H, dd, J=7.3 and 1.5 Hz), 8.00-8.13 (3H, m); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₂S: 409.1; found [M+H]⁺: 410.1.

Example 39: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-2-(trifluoromethyl)benzenesulfonamide—Compound (ZDR075)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.49 mmol), 2-(trifluoromethyl)benzenesulfonyl chloride (84 μL, 0.54 mmol) and triethylamine (76 μL, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR075) as a pale orange solid (70 mg, 0.17 mmol, 34%). ¹H NMR (300 MHz, CDCl₃) δ 2.29 (6H, s), 3.70 (2H, s), 7.37-7.46 (2H, m), 7.52-7.56 (2H, m), 7.61 (1H, d, J=8.5 Hz), 7.75-7.78 (1H, m), 7.85 (1H, dd, J=7.2 and 1.7 Hz), 8.05 (1H, d, J=8.5 Hz), 8.18-8.21 (1H, m); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₂S: 409.1; found [M+H]⁺: 410.1.

Example 40: 3-cyano-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR076)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.49 mmol), 3-cyanobenzenesulfonyl chloride (110 mg, 0.54 mmol) and triethylamine (76 μL, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR076) as a pale orange solid (93 mg, 0.25 mmol, 51%). ¹H NMR (300 MHz, CDCl₃) δ 2.21 (6H, s), 3.72 (2H, s), 7.41-7.52 (3H, m), 7.59 (1H, d, J=8.4 Hz) 7.65-7.68 (1H, m), 7.82 (1H, dd, J=7.4 and 1.4 Hz), 8.06-8.09 (2H, m), 8.17-8.18 (1H, m); ESI-MS: m/z calcd for C₁₉H₁₈N₄O₂S: 366.1; found [M+H]⁺: 367.1.

Example 41: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-2-cyanobenzenesulfonamide—Compound (ZDR077)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.49 mmol), 2-cyanobenzenesulfonyl chloride (110 mg, 0.54 mmol) and triethylamine (76 μL, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1) afforded compound (ZDR077) as a pale orange solid (117 mg, 0.31 mmol, 63%). ¹H NMR (300 MHz, CDCl₃) δ 2.32 (6H, s), 3.80 (2H, s), 7.34-7.70 (6H, m), 7.74 (1H, dd, J=7.6 and 1.3 Hz), 8.05 (1H, d, J=8.4 Hz), 8.14 (1H, dd, J=7.6 and 1.3 Hz); ESI-MS: m/z calcd for C₁₉H₁₈N₄O₂S: 366.1; found [M+H]⁺: 367.1.

Example 42: N-(2-((Dimethylamino)methyl)quinolin-8-yl)methanesulfonamide—Compound (ZDR078)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.49 mmol), methanesulfonyl chloride (42 μL, 0.54 mmol) and triethylamine (76 μL, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR078) as a pale yellow solid (99 mg, 0.35 mmol, 71%). ¹H NMR (300 MHz, CDCl₃) δ 2.34 (6H, s), 3.03 (3H, s), 3.77 (2H, s), 7.47-7.54 (2H, s), 7.62 (1H, d, J=8.4 Hz), 7.81 (1H, dd, J=7.2 and 1.6 Hz), 8.13 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₃H₁₇N₃O₂S: 279.1; found [M+H]⁺: 280.1.

Example 43: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-1,1,1-trifluoromethanesulfonamide—Compound (ZDR079)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.49 mmol), trifluoromethanesulfonyl chloride (58 μL, 0.54 mmol) and triethylamine (76 μL, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR079) as a beige solid (82 mg, 0.24 mmol, 48%). ¹H NMR (300 MHz, d₄-MeOH) δ 2.98 (6H, s), 4.57 (2H, s), 7.33 (1H, d, J=8.4 Hz), 7.42-7.46 (2H, m), 7.76-7.81 (1H, m), 8.22 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₃H₁₄F₃N₃O₂S: 333.1; found [M+H]⁺: 334.1.

Example 44: N-(2-((Dimethylamino)methyl)quinolin-8-yl)thiophene-2-sulfonamide—Compound (ZDR080)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.49 mmol), 2-thiophenesulfonyl chloride (99 mg, 0.54 mmol) and triethylamine (76 μL, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR080) as a beige solid (93 mg, 0.26 mmol, 53%). ¹H NMR (300 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 6.85-6.88 (1H, m), 7.36-7.47 (3H, m), 7.56-7.59 (2H, m), 7.87 (1H, dd, J=7.1 and 1.8 Hz), 8.06 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₆H₁₇N₃O₂S₂: 347.1; found [M+H]⁺: 348.1.

Example 45: N-(2-((Dimethylamino)methyl)quinolin-8-yl)thiophene-3-sulfonamide—Compound (ZDR081)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.49 mmol), 3-thiophenesulfonyl chloride (99 mg, 0.54 mmol) and triethylamine (76 μL, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR081) as a tan solid (87 mg, 0.25 mmol, 51%). ¹H NMR (300 MHz, CDCl₃) δ 2.30 (6H, s), 3.71 (2H, s), 7.18 (1H, dd, J=5.1 and 3.0 Hz), 7.28 (1H, dd, J=5.1 and 1.2 Hz), 7.39-7.49 (2H, m), 7.59 (1H, d, J=8.4 Hz), 7.83 (1H, dd, J=7.1 and 1.7 Hz), 7.97 (1H, d, J=3.0 and 1.2 Hz), 8.07 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₆H₁₇N₃O₂S₂: 347.1; found [M+H]⁺: 348.1.

Example 46: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3,5-dimethylisoxazole-4-sulfonamide—Compound (ZDR082)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.49 mmol), 3,5-dimethylisoxazole-4-sulfonyl chloride (105 mg, 0.54 mmol) and triethylamine (76 μL, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR082) as a pale orange solid (95 mg, 0.26 mmol, 53%). ¹H NMR (300 MHz, CDCl₃) δ 2.29 (6H, s), 2.38 (3H, s), 2.53 (3H, s), 3.70 (2H, s), 7.42 (1H, t, J=7.8 Hz), 7.53 (1H, dd, J=7.8 and 1.3 Hz), 7.62 (1H, d, J=8.4 Hz), 7.77 (1H, dd, J=7.8 and 1.3 Hz), 8.10 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₇H₂₀N₄O₃S: 360.1; found [M+H]⁺: 361.1.

Example 47: 3-Chloro-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR084)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 3-chlorobenzenesulfonyl chloride (68 μL, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR084) as a pale yellow solid (109 mg, 0.28 mmol, 63%). ¹H NMR (300 MHz, CDCl₃) δ 2.31 (6H, s), 3.74 (2H, s), 7.25 (1H, t, J=7.8 Hz), 7.35-7.50 (3H, m), 7.57 (1H, d, J=8.4 Hz), 7.73-7.76 (1H, m), 7.82 (1H, dd, J=7.2 and 1.6 Hz), 7.90-7.92 (1H, m), 8.07 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₈ClN₃O₂S: 375.1; found [M+H]⁺: 376.1.

Example 48: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3-(trifluoromethoxy)benzenesulfonamide—Compound (ZDR085)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 3-(trifluoromethoxy)benzenesulfonyl chloride (83 μL, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR085) as a pale orange solid (101 mg, 0.23 mmol, 52%). ¹H NMR (300 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 7.20-7.27 (1H, m), 7.33-7.51 (3H, m), 7.58 (1H, d, J=8.4 Hz), 7.69-7.73 (1H, m), 7.79-7.85 (2H, m), 8.06 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₃S: 425.1; found [M+H]⁺: 426.1.

Example 49: N-(2-((Cyclopropylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR086)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), cyclopropylamine (54 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR086) as a pale yellow solid (70 mg, 0.16 mmol, 61%). ¹H NMR (300 MHz, CDCl₃) δ 0.43-0.47 (4H, m), 2.15-2.19 (1H, m), 4.10 (2H, s), 7.38-7.50 (3H, m), 7.59 (2H, d, J=8.2 Hz), 7.82 (1H, dd, J=7.3 and 1.4 Hz), 8.00 (2H, d, J=8.2 Hz), 8.04 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₁₈F₃N₃O₂S: 421.1; found [M+H]⁺: 422.1.

Example 50: N-(2-(((Cyclopropylmethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR087)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), cyclopropylmethylamine (68 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→10:1) afforded compound (ZDR087) as a pale yellow solid (83 mg, 19 mmol, 73%). ¹H NMR (300 MHz, CDCl₃) δ 0.18-0.22 (2H, m), 0.48-0.54 (2H, m), 1.01-1.14 (1H, m), 2.77 (2H, d, J=7.0 Hz), 4.35 (2H, s), 7.33-7.44 (5H, m), 7.70 (1H, dd, J=7.0 and 1.9 Hz), 7.86 (2H, d, J=8.2 Hz), 8.03 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₁H₂₀F₃N₃O₂S: 435.1; found [M+H]⁺: 436.1.

Example 51: N-(2-(Thiomorpholinomethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR088)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), thiomorpholine (79 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR088) as a pale yellow solid (55 mg, 0.11 mmol, 42%). ¹H NMR (300 MHz, CDCl₃) δ 2.65-2.78 (8H, m), 3.76 (2H, s), 7.39-7.50 (2H, m), 7.57-7.62 (3H, m), 7.82 (1H, dd, J=7.3 and 1.5 Hz), 8.00 (2H, d, J=8.1 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₁H₂₀F₃N₃O₂S₂: 467.1; found [M+H]⁺: 468.1.

Example 52: N-(2-((4-Methylpiperazin-1-yl)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR089)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 1-methylpiperazine (87 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1→10:1) afforded compound (ZDR089) as a white solid (77 mg, 0.16 mmol, 61%). ¹H NMR (300 MHz, CDCl₃) δ 2.31 (3H, s), 2.40-2.60 (8H, m), 3.76 (2H, s), 7.39-7.50 (2H, m), 7.57-7.63 (3H, in), 7.82 (1H, dd, J=7.3 and 1.5 Hz), 7.99 (2H, d, J=8.1 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₂H₂₃F₃N₄O₂S: 464.1; found [M+H]⁺:465.1.

Example 53: N-(2-(((3-(Dimethylamino)propyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide di-trifluoroacetate—Compound (ZDR090)

A solution of (ZDR019) (100 mg, 0.26 mmol), 3-(dimethylamino)-1-propylamine (99 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 18 h, and the solvent removed in vacuo. Purification by RP-HLPC (10% to 20% A/B gradient over 20 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR090) as a white solid (36 mg, 0.05 mmol, 19%). ¹H NMR (300 MHz, CDCl₃) δ 1.79 (2H, t, J=7.0 Hz), 2.27 (6H, s), 2.43 (2H, t, J=7.0 Hz), 2.81 (2H, t, J=7.0 Hz), 4.10 (2H, s), 7.37-7.47 (3H, m), 7.56 (2H, d, J=8.2 Hz), 7.77 (1H, dd, J=7.3 and 1.5 Hz), 8.00 (2H, d, J=8.2 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₂H₂₅F₃N₄O₂S: 466.2; found [M+H]⁺: N/A.

Example 54: N-(2-(((3-Hydroxypropyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR091)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 3-amino-1-propanol (60 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→15:1→10:1) afforded compound (ZDR091) as a white solid (60 mg, 0.13 mmol, 50%). ¹H NMR (300 MHz, d₆-DMSO) δ 1.76-1.83 (2H, m), 2.87 (2H, t, J=6.5 Hz), 3.53 (2H, t, J=6.5 Hz), 4.25 (2H, s), 7.38 (1H, t, J=7.7 Hz), 7.44-7.58 (4H, m), 7.63 (1H, dd, J=7.4 and 1.1 Hz), 7.83 (2H, d, J=8.0 Hz), 8.19 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₀F₃N₃O₃S: 439.1; found [M+H]⁺:440.1.

Example 55: N-(2-(((1,3-Dihydroxypropan-2-yl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR092)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), serinol (71 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1→8:1) afforded compound (ZDR092) as a pale yellow solid (50 mg, 0.10 mmol, 38%). ¹H NMR (300 MHz, CDCl₃) δ 3.06-3.18 (1H, m), 3.79-3.99 (4H, m), 4.32 (2H, s), 7.24-7.41 (3H, m), 7.55 (2H, d, J=8.2 Hz), 7.75 (1H, dd, J=7.0 and 1.8 Hz), 7.97 (1H, d, J=8.4 Hz), 8.02 (2H, d, J=8.2 Hz); ESI-MS: m/z calcd for C₂₀H₂₀F₃N₃O₄S: 455.1; found [M+H]⁺: 456.1.

Example 56: N-(2-(((2,3-Dihydroxypropyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR093

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), (±)-3-amino-1,2-propanediol (71 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1→48:1) afforded compound (ZDR093) as a pale yellow solid (60 mg, 0.13 mmol, 50%). ¹H NMR (300 MHz, CDCl₃) δ 2.85-3.00 (2H, m), 3.65-3.82 (2H, m), 4.06-4.20 (3H, m), 7.20 (1H, d, J=8.4 Hz), 7.29-7.37 (2H, m), 7.46 (2H, d, J=8.2 Hz), 7.71 (1H, dd, J=7.0 and 1.9 Hz), 7.90 (1H, d, J=8.4 Hz), 7.98 (2H, d, J=8.2 Hz); ESI-MS: m/z calcd for C₂₀H₂₀F₃N₃O₄S: 455.1; found [M+H]⁺: 456.1.

Example 57: N-(2-((Bis(2-hydroxyethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR094)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), diethanolamine (78 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 30:1→20:1→15:1) afforded compound (ZDR094) as a white solid (30 mg, 0.06 mmol, 23%). ¹H NMR (300 MHz, CDCl₃) δ 2.87 (4H, t, J=5.0 Hz), 3.69 (4H, t, J=5.0 Hz), 4.04 (2H, s), 7.39-7.49 (3H, m), 7.62 (2H, d, J=8.3 Hz), 7.85 (1H, dd, J=7.2 and 1.5 Hz), 8.03-8.09 (3H, m); ESI-MS: m/z calcd for C₂₁H₂₂F₃N₃O₄S: 469.1; found [M+H]⁺: 470.1.

Example 58: N-(2-(((2-(Pyridin-2-yl)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR095)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-(2-pyridyl)ethylamine (94 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1) afforded compound (ZDR095) as a pale orange solid (77 mg, 0.15 mmol, 57%). ¹H NMR (300 MHz, CDCl₃) δ 3.21 (2H, t, J=6.5 Hz), 3.38 (2H, t, J=6.5 Hz), 4.36 (2H, s), 7.11-7.20 (2H, m), 7.36-7.46 (3H, m), 7.54-7.63 (3H, m), 7.78 (1H, dd, J=7.2 and 1.6 Hz), 8.03-8.07 (3H, m), 8.55-8.57 (1H, m); ESI-MS: m/z calcd for C₂₄H₂₁F₃N₄O₂S: 486.1; found [M+H]⁺: 487.1.

Example 59: N-(2-((Bis(pyridin-2-ylmethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR096)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), di-(2-picoyl)amine (141 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR096) as a tan solid (66 mg, 0.11 mmol, 42%). ¹H NMR (300 MHz, CDCl₃) δ 3.86 (4H, s), 3.94 (2H, s), 7.15-7.26 (2H, m), 7.37-7.47 (2H, m), 7.52-7.59 (5H, m), 7.66-7.71 (2H, m), 7.87 (1H, dd, J=7.2 and 1.6 Hz), 8.00-8.05 (3H, m), 8.62-8.64 (2H, m); ESI-MS: m/z calcd for C₂₉H₂₄F₃N₅O₂S: 563.2; found [M+H]⁺: 564.2.

Example 60: N-(2-((Allylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR097)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), allyamine (59 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR097) as a pale yellow solid (62 mg, 0.14 mmol, 53%). ¹H NMR (300 MHz, CDCl₃) δ 3.35-3.38 (2H, m), 4.09 (2H, s), 5.15-5.29 (2H, m), 5.91-5.97 (1H, m), 7.37-7.48 (3H, m), 7.53 (2H, d, J=8.2 Hz), 7.95 (1H, dd, J=7.3 and 1.5 Hz), 7.93 (2H, d, J=8.2 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₁₈F₃N₃O₂S: 421.1; found [M+H]⁺: 422.1.

Example 61: N-(2-((Prop-2-yn-1-ylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR098)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), propargylamine (50 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (petroleum ether/ethyl acetate, 1:1→1:2) afforded compound (ZDR098) as a pale yellow solid (66 mg, 0.15 mmol, 57%). ¹H NMR (300 MHz, CDCl₃) δ 2.32 (1H, t, J=2.4 Hz), 3.50 (2H, d, J=2.4 Hz), 4.15 (2H, s), 7.39-7.50 (3H, m), 7.59 (2H, d, J=8.2 Hz), 7.83 (1H, dd, J=7.3 and 1.5 Hz), 8.00 (2H, d, J=8.2 Hz), 8.06 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₁₆F₃N₃O₂S: 419.1; found [M+H]⁺: 420.1.

Example 62: N-(2-(((2-Fluoroethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR099)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-fluoroethylamine hydrochoride (77 mg, 0.78 mmol), triethylamine (109 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1→50:1) afforded compound (ZDR099) as a beige solid (50 mg, 0.11 mmol, 42%). ¹H NMR (300 MHz, CDCl₃) δ 4.10 (2H, s), 2.98 (2H, dt, J=28.5 and 4.7 Hz), 4.62 (2H, dt, J=47.5 and 4.7 Hz), 7.39-7.50 (3H, m), 7.59 (2H, d, J=8.2 Hz), 7.84 (1H, dd, J=7.3 and 1.5 Hz), 7.99 (2H, d, J=8.2 Hz), 8.06 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₁₇F₄N₃O₂S: 427.1; found [M+H]⁺: 428.1.

Example 63: N-(2-(((2,2-Difluoroethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound ZDR100)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2,2-difluoroethylamine (63 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1→50:1) afforded compound (ZDR100) as a beige solid (49 mg, 0.11 mmol, 42%). ¹H NMR (300 MHz, CDCl₃) δ 3.03 (2H, td, J=15.1 and 4.2 Hz), 4.11 (2H, s), 5.91 (1H, tt, J=56.3 and 4.2 Hz), 7.41-7.51 (3H, m), 7.61 (2H, d, J=8.2 Hz), 7.86 (1H, dd, J=7.3 and 1.5 Hz), 8.01 (2H, d, J=8.2 Hz), 8.08 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₁₆F₅N₃O₂S: 445.1; found [M+H]⁺: 446.1.

Example 64: N-(2-(((Pyridin-3-ylmethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR101)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 3-picolylamine (80 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL).

Purification by flash chromatography (dichloromethane/methanol, 100:1→50:1) afforded compound (ZDR101) as a pale yellow solid (59 mg, 0.12 mmol, 46%). ¹H NMR (300 MHz, CDCl₃) δ 3.89 (2H, s), 4.06 (2H, s), 7.25-7.29 (1H, m), 7.38-7.50 (3H, m), 7.58 (2H, d, J=8.2 Hz), 7.70-7.75 (1H, m), 7.80 (1H, dd, J=7.3 and 1.5 Hz), 7.99 (2H, d, J=8.2 Hz), 8.06 (1H, d, J=8.5 Hz), 8.50-8.52 (1H, m), 8.59 (1H, d, J=1.8 Hz); ESI-MS: m/z calcd for C₂₃H₁₉F₃N₄O₂S: 472.1; found [M+H]⁺: 473.1.

Example 65: N-(2-(((1,3-Dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR102)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), tris(hydroxymethyl)aminomethane (94 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1→50:1) afforded compound (ZDR102) as a pale yellow solid (38 mg, 0.07 mmol, 26%). ¹H NMR (300 MHz, CDCl₃) δ 3.70 (6H, s), 4.18 (2H, s), 7.17-7.30 (3H, m), 7.41 (2H, d, J=8.2 Hz), 7.60 (1H, dd, J=7.2 and 1.8 Hz), 7.82 (1H, d, J=8.4 Hz), 7.93 (2H, d, J=8.2 Hz); ESI-MS: m/z calcd for C₂₁H₂₂F₃N₃O₅S: 485.1; found [M+H]⁺: 486.1.

Example 66: N-(2-((Benzylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide)—Compound (ZDR103)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), benzylamine (86 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1→50:1) afforded compound (ZDR103) as a pale yellow solid (60 mg, 0.12 mmol, 46%). ¹H NMR (300 MHz, CDCl₃) δ 3.88 (2H, s), 4.07 (2H, s), 7.27-7.54 (10H, m), 7.82 (1H, dd, J=7.3 and 1.5 Hz), 7.94 (2H, d, J=8.3 Hz), 8.06 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₄H₂₀F₃N₃O₂S: 471.1; found [M+H]⁺: 472.1.

Example 67: N-(2-(((Furan-2-ylmethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR106)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), furfurylamine (69 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane→dichloromethane/methanol, 100:1) afforded compound (ZDR106) as a pale orange solid (62 mg, 0.13 mmol, 50%). ¹H NMR (300 MHz, CDCl₃) δ 3.87 (2H, s), 4.08 (2H, s), 6.23-6.25 (1H, m), 6.32-6.35 (1H, m), 7.35-7.49 (4H, m), 7.54 (2H, d, J=8.2 Hz), 7.83 (1H, dd, J=7.3 and 1.4 Hz), 7.94 (2H, d, J=8.2 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₂H₁₈F₃N₃O₃S: 461.1; found [M+H]⁺: 462.1.

Example 68: N-(2-(((Thiophen-2-ylmethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR107)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-thiophenemethylamine (80 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane→dichloromethane/methanol, 100:1) afforded compound (ZDR107) as a pale orange solid (70 mg, 0.14 mmol, 53%). ¹H NMR (300 MHz, CDCl₃) δ 4.09 (2H, s), 4.11 (2H, s), 6.99-7.01 (2H, m), 7.26-7.28 (1H, m), 7.41-7.52 (3H, m), 7.57 (2H, d, J=8.2 Hz), 7.84 (1H, dd, J=7.4 and 1.4 Hz), 7.99 (2H, d, J=8.2 Hz), 8.07 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₂H₁₈F₃N₃O₂S₂: 477.1; found [M+H]⁺:478.1.

Example 69: N-(2-((Phenylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR108)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), aniline (72 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane) afforded compound (ZDR108) as a beige solid (23 mg, 0.05 mmol, 19%). ¹H NMR (300 MHz, CDCl₃) δ 4.62 (2H, s), 6.75-6.78 (3H, m), 7.18-7.21 (2H, m), 7.41 (1H, t, J=7.9 Hz), 7.46-7.50 (2H, m), 7.54 (2H, d, J=8.2 Hz), 7.83 (1H, dd, J=7.3 and 1.6 Hz), 7.91 (2H, d, J=8.2 Hz), 8.05 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₂₃H₁₈F₃N₃O₂S: 457.1; found [M+H]⁺: 458.1.

Example 70: N-(2-((Pyridin-2-ylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR109)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-aminopyridine (73 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (petroleum ether/ethyl acetate, 2:1) afforded compound (ZDR109) as a pale yellow solid (20 mg, 0.04 mmol, 15%). ¹H NMR (300 MHz, CDCl₃) δ 4.76 (2H, d, J=5.7 Hz), 5.56-5.64 (1H, m), 6.53 (1H, d, J=8.4 Hz), 6.62-6.66 (1H, m), 7.38-7.56 (6H, m), 7.83 (1H, dd, J=7.3 and 1.4 Hz), 7.94 (2H, d, J=8.2 Hz), 8.04 (1H, d, J=8.4 Hz), 8.11-8.13 (1H, m); ESI-MS: m/z calcd for C₂₂H₁₇F₃N₄O₂S: 458.1; found [M+H]⁺: 459.1.

Example 71: N-(2-(((Pyridin-4-ylmethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR110)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 4-(aminomethyl)pyridine (79 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR110) as a pale orange solid (44 mg, 0.09 mmol, 34%). ¹H NMR (300 MHz, CDCl₃) δ 3.89 (2H, s), 4.06 (2H, s), 7.30-7.34 (2H, m), 7.39-7.50 (3H, m), 7.58 (2H, d, J=8.2 Hz), 7.81 (1H, dd, J=7.4 and 1.5 Hz), 7.99 (2H, d, J=8.2 Hz), 8.07 (1H, d, J=8.4 Hz), 8.56-8.58 (2H, m); ESI-MS: m/z calcd for C₂₃H₁₉F₃N₄O₂S: 472.1; found [M+H]⁺: 473.0.

Example 72: N-(2-(((2-(Piperidin-1-yl)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR111)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 1-(2-aminoethyl)piperidine (112 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→20:1→10:1→7:1) afforded compound (ZDR111) as a pale yellow solid (70 mg, 0.14 mmol, 53%). ¹H NMR (300 MHz, CDCl₃) δ 1.44-1.54 (2H, m), 1.64-1.76 (4H, m), 2.66-2.76 (4H, m), 2.90 (2H, t, J=6.2 Hz), 3.03 (2H, t, J=6.2 Hz), 4.19 (2H, s), 7.34-7.43 (3H, m), 7.55 (2H, d, J=8.2 Hz), 7.74 (1H, dd, J=7.2 and 1.5 Hz), 8.01 (1H, d, J=8.4 Hz), 8.06 (2H, d, J=8.2 Hz); ESI-MS: m/z calcd for C₂₄H₂₇F₃N₄O₂S: 492.2; found [M+Na]⁺: 515.2.

Example 73: N-(2-(((2-Morpholinoethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR112)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 4-(2-aminoethyl)morpholine (103 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→20:1) afforded compound (ZDR112) as a pale yellow solid (80 mg, 0.16 mmol, 61%). ¹H NMR (300 MHz, CDCl₃) δ 2.43-2.46 (4H, m), 2.58 (2H, t, J=6.2 Hz), 2.83 (2H, t, J=6.2 Hz), 3.68-3.71 (4H, m), 4.14 (2H, s), 7.37-7.49 (3H, m), 7.58 (2H, d, J=8.2 Hz), 7.78 (1H, dd, J=7.3 and 1.5 Hz), 8.01 (2H, d, J=8.2 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₃H₂₅F₃N₄O₃S: 494.2; found [M+H]⁺: N/A.

Example 74: N-(2-(((2-Thiomorpholinoethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR113)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 4-(2-aminoethyl)thiomorpholine (109 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→20:1) afforded compound (ZDR113) as a pale orange solid (70 mg, 0.13 mmol, 50%). ¹H NMR (300 MHz, CDCl₃) δ 2.59 (2H, t, J=5.9 Hz), 2.63-2.75 (8H, m), 2.80 (2H, t, J=5.9 Hz), 4.12 (2H, s), 7.37-7.48 (3H, m), 7.58 (2H, d, J=8.2 Hz), 7.78 (1H, dd, J=7.3 and 1.4 Hz), 8.02 (2H, d, J=8.2 Hz), 8.06 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₃H₂₅F₃N₄O₂S₂: 510.1; found [M+H]⁺: 511.1.

Example 75: N-(2-(((2-(4-Methylpiperazin-1-yl)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide di-trifluoroacetate—Compound (ZDR114)

A similar procedure to that described for the preparation of compound (ZDR090) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 1-(2-aminoethyl)-4-methylpiperazine (118 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by RP-HLPC (10% to 20% A/B gradient over 20 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR114) as a white solid (50 mg, 0.06 mmol, 23%). ¹H NMR (300 MHz, CDCl₃) δ 2.31 (3H, s), 2.47-2.57 (8H, m), 2.58 (2H, t, J=6.9 Hz), 2.78 (2H, t, J=6.9 Hz), 4.07 (2H, s), 7.38-7.49 (3H, m), 7.61 (2H, d, J=8.2 Hz), 7.80 (1H, dd, J=7.4 and 1.4 Hz), 8.0-8.07 (3H, m); ESI-MS: m/z calcd for C₂₄H₂₈F₃N₅O₂S: 507.2; found [M+H]⁺: N/A.

Example 76: N-(2-(((3-(Piperidin-1-yl)propyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide di-trifluoroacetate—Compound (ZDR115)

A similar procedure to that described for the preparation of compound (ZDR090) was followed using compound (ZDR019) (100 mg, 0.26 mmol), N-(3-aminopropyl)piperidine (125 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by RP-HLPC (10% to 20% A/B gradient over 20 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR115) as a white solid (70 mg, 0.10 mmol, 38%). ¹H NMR (300 MHz, CDCl₃) δ 1.40-1.50 (2H, m), 1.58-1.69 (4H, m), 1.86-1.95 (2H, m), 2.58-2.73 (6H, m), 2.86 (2H, t, J=6.9 Hz), 4.12 (2H, s), 7.36-7.46 (3H, m), 7.56 (2H, d, J=8.2 Hz), 7.74 (1H, dd, J=7.3 and 1.5 Hz), 8.01 (2H, d, J=8.2 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₅H₂₉F₃N₄O₂S: 506.2; found [M+H]⁺: 507.2.

Example 77: N-(2-(((3-Morpholinopropyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR116)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 3-(4-morpholinyl)-1-propanamine (112 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR116) as a pale orange solid (92 mg, 0.18 mmol, 69%). ¹H NMR (300 MHz, CDCl₃) δ 1.88 (2H, t, J=6.9 Hz), 2.42-2.48 (6H, m), 2.93 (2H, t, J=6.9 Hz), 3.60-3.64 (4H, m), 4.21 (2H, s), 7.38-7.43 (3H, m), 7.53 (2H, d, J=8.2 Hz), 7.75 (1H, dd, J=7.2 and 1.6 Hz), 8.02-8.06 (3H, m); ESI-MS: m/z calcd for C₂₄H₂₇F₃N₄O₃S: 508.2; found [M+H]⁺: 509.2.

Example 78: N-(2-(((3-(4-Methylpiperazin-1-yl)propyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide di-trifluoroacetate—Compound (ZDR117)

A similar procedure to that described for the preparation of compound (ZDR090) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 1-(3-aminopropyl)-4-methylpiperazine (134 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by RP-HLPC (10% to 20% A/B gradient over 20 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR117) as a white solid (44 mg, 0.06 mmol, 23%). ¹H NMR (300 MHz, CDCl₃) δ 1.79 (2H, t, J=6.9 Hz), 2.22 (3H, s), 2.35-2.55 (8H, m), 2.45 (2H, t, J=6.9 Hz), 2.80 (2H, t, J=6.9 Hz), 4.10 (2H, s), 7.36-7.46 (3H, m), 7.55 (2H, d, J=8.2 Hz), 7.76 (1H, dd, J=7.3 and 1.5 Hz), 8.01 (2H, d, J=8.2 Hz), 8.04 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₅H₃₀F₃N₅O₂S: 521.2; found [M+H]⁺: 522.2.

Example 79: (E)-2-((8-((4-(Trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methylene)hydrazine-1-carboxamide—Compound (ZDR118)

A solution of compound (ZDR019) (100 mg, 0.26 mmol), semicarbazide hydrochloride (29 mg, 0.26 mmol) and sodium acetate (43 mg, 0.52 mmol) in aqueous ethanol (5 mL, 90% v/v) was heated at 70° C. for 18 h. The mixture was then diluted with dichloromethane/methanol (25 mL, 9:1 v/v), water (25 mL) added and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR118) as a white solid (85 mg, 0.19 mmol, 73%). ¹H NMR (300 MHz, CDCl₃) δ 7.19-7.22 (1H, m), 7.29 (1H, t, J=7.6 Hz), 7.61-7.66 (3H, m), 7.85 (1H, d, J=8.4 Hz), 8.02-8.07 (4H, m), 11.22 (1H, s); ESI-MS: m/z calcd for C₁₈H₁₄F₃N₅O₃S: 437.1; found [M+Na]⁺: 460.1.

Example 80: (E)-N-(2-Morpholinoethyl)-2-((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methylene)hydrazine-1-carbothioamide—Compound (ZDR119)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol) and 4-[2-(4-morpholinyl)ethyl]-3-thiosemicarbazide (53 mg, 0.26 mmol) in aqueous ethanol (5 mL, 90% v/v). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR119) as a pale yellow solid (95 mg, 0.16 mmol, 61%). ¹H NMR (400 MHz, CDCl₃) δ 2.58 (4H, brs), 2.72 (2H, t, J=5.8 Hz), 3.76-3.80 (4H, m), 3.84 (2H, q, J=5.8 Hz), 7.47-7.52 (2H, m), 7.65 (2H, d, J=8.5 Hz), 7.86 (1H, dd, J=6.7 and 2.3 Hz), 8.01-8.06 (4H, m), 8.13 (1H, d, J=8.5 Hz), 8.30 (1H, brs), 9.15 (1H, brs), 9.78 (1H, brs); ESI-MS: m/z calcd for C₂₄H₂₅F₃N₆O₃S₂: 566.1; found [M+H]⁺: 567.1.

Example 81: (E/Z)—N-(2-((2-Acetylhydrazineylidene)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR120)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol) and acetylhydrazide (19 mg, 0.26 mmol) in aqueous ethanol (5 mL, 90% v/v). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR120) as a white solid (90 mg, 0.20 mmol, 76%), as a 1:1 mixture of E/Z isomers. ¹H NMR (300 MHz, CDCl₃/d₄-MeOH, 1:1 v/v) δ 2.14 (1.5H, s), 2.36 (1.5H, s), 7.41-7.56 (2H, m), 7.60 (2H, d, J=8.2 Hz), 7.77-7.82 (1H, m), 7.95-8.03 (3H, m), 8.10-8.17 (2H, m); ESI-MS: m/z calcd for C₁₉H₁₅F₃N₄O₃S: 436.1; found [M+Na]⁺: 459.1.

Example 82: (E)-N-(2-((2-Nicotnoylhydrazineylidene)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR121)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol) and nicotinic acid hydrazide (36 mg, 0.26 mmol) in aqueous ethanol (5 mL, 90% v/v). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR121) as a white solid (85 mg, 0.17 mmol, 65%). ¹H NMR (300 MHz, d₆-DMSO) δ 7.56-7.85 (6H, m), 7.98-8.08 (3H, m), 8.24-8.42 (2H, m), 8.50 (1H, s), 8.74-8.85 (1H, m), 8.95-9.14 (1H, m), 10.41 (1H, br s), 12.39 (1H, s); ESI-MS: m/z calcd for C₂₃H₁₆F₃N₅O₃S: 499.1; found [M+Na]⁺: 522.1.

Example 83: (E)-N-(2-((2-Isonicotinoylhydrazneylidene)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR122)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol) and isonicotinic acid hydrazide (36 mg, 0.26 mmol) in aqueous ethanol (5 mL, 90% v/v). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR122) as a yellow solid (83 mg, 0.16 mmol, 61%). ¹H NMR (300 MHz, d₆-DMSO) δ 7.56-7.88 (7H, m), 8.00-8.07 (3H, m), 8.37 (1H, d, J=8.4 Hz), 8.53 (1H, s), 8.75-8.87 (2H, m), 12.44 (1H, s); ESI-MS: m/z calcd for C₂₃H₁₆F₃N₅O₃S: 499.1; found [M+Na]⁺: 522.1.

Example 84: tert-Butyl (E/Z)-3-(2-((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methylene)hydrazine-1-carbonyl)piperidine-1-carboxylate—Compound ZDR123

A similar procedure to a described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol) and 1-Boc-nipecotic acid hydrazide (63 mg, 0.26 mmol) in aqueous ethanol (5 mL, 90% v/v). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR123) as a white solid (97 mg, 0.16 mmol, 61%). ESI-MS: m/z calcd for C₂₉H₃₀F₃N₅O₅S: 605.2; found [M+Na]⁺: 628.2.

Example 85: (E/Z)—N-(2-((2-(Piperidine-3-carbonyl)hydrazineylidene)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide trifluoroacetate—Compound (ZDR124)

A solution of compound (ZDR123) (50 mg, 0.08 mmol) in trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) was stirred at room temperature for 3 h. The solvent was removed in vacuo to afford compound (ZDR124) as a white solid (48 mg, 0.08 mmol, quant.), as a 1:1 mixture of E/Z isomers, which was used without further purification. ¹H NMR (400 MHz, d₄-MeOH) δ 1.85-2.06 (3H, m), 2.12-2.20 (1H, m), 2.98 (0.5H, sept, J=4.1 Hz), 3.14-3.21 (1H, m), 3.26-3.31 (1H, m), 3.37-3.44 (2H, m), 3.82 (0.5H, sept, J=4.1 Hz), 7.50-7.56 (1H, m), 7.62-7.66 (3H, m), 7.86 (1H, dt, J=7.5 and 1.3 Hz), 7.95-7.99 (2H, m), 8.01 (0.5H, d, J=8.6 Hz), 8.04 (0.5H, s), 8.10 (0.5H, d, J=8.6 Hz), 8.21 (1H, dd, J=8.6 and 1.6 Hz), 8.25 (0.5H, s); ESI-MS: m/z calcd for C₂₅H₂₂F₃N₅O₄S: 505.1; found [M+H]⁺: N/A.

Example 86: (E)-N-(2-((Hydroxyimino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR125)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol) and hydroxylamine hydrochloride (18 mg, 0.26 mmol) in aqueous ethanol (10 mL, 60% v/v). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR125) as a white solid (80 mg, 0.20 mmol, 76%). ¹H NMR (300 MHz, CDCl₃) δ 6.90 (1H, d, J=8.4 Hz), 7.36-7.61 (5H, m), 7.76 (1H, dd, J=7.3 and 1.4 Hz), 7.92 (2H, d, J=8.2 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₇H₁₂F₃N₃O₃S: 395.1; found [M+H]⁺: N/A.

Example 87: (E)-N-(2-((Methoxyimino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR126)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol), methoxyamine hydrochloride (21 mg, 0.26 mmol) and sodium acetate (43 mg, 0.52 mmol) in ethanol (10 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR126) as a white solid (75 mg, 0.18 mmol, 69%). ¹H NMR (300 MHz, CDCl₃) δ 4.07 (3H, s), 7.43-7.49 (2H, m), 7.62 (2H, d, J=8.4 Hz), 7.84 (1H, dd, J=7.2 and 1.5 Hz), 7.97-8.07 (4H, m), 8.21 (1H, s), 9.12 (1H, br s); ESI-MS: m/z calcd for C₁₈H₁₄F₃N₃O₃S: 409.1; found [M+Na]⁺: 432.1.

Example 88: (E)-N-(2-(Hydrazineylidenemethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR127)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol) and aqueous hydrazine (1 mL, 50% w/w in water) in ethanol (10 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR127) as a yellow solid (66 mg, 0.16 mmol, 61%). ¹H NMR (400 MHz, CDCl₃) δ 6.00 (2H, s), 7.40 (1H, t, J=8.0 Hz), 7.46 (1H, dd, J=8.2 and 1.4 Hz), 7.62 (2H, d, J=8.4 Hz), 7.80 (1H, dd, J=7.6 and 1.4 Hz), 7.89 (1H, s), 7.96-8.04 (4H, m); ESI-MS: m/z calcd for C₁₇H₁₃F₃N₄O₂S: 394.1; found [M+H]⁺: 395.1.

Example 89: N-(2-(((2-(2-Hydroxyethoxy)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR129)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-(2-aminoethoxy)ethanol (79 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→20:1→15:1) afforded compound (ZDR129) as a pale orange solid (81 mg, 0.17 mmol, 65%). ¹H NMR (300 MHz, CDCl₃) δ 2.98 (2H, t, J=5.0 Hz), 3.70 (2H, t, J=5.0 Hz), 3.76 (2H, t, J=5.0 Hz), 3.84 (2H, t, J=5.0 Hz), 4.16 (2H, s), 7.29 (1H, d, J=8.4 Hz), 7.34-7.42 (2H, m), 7.56 (2H, d, J=8.3 Hz), 7.79 (1H, dd, J=7.0 and 1.9 Hz), 7.96 (1H, d, J=8.4 Hz), 8.03 (2H, d, J=8.3 Hz); ESI-MS: m/z calcd for C₂₁H₂₂F₃N₃O₄S: 469.1; found [M+H]⁺: 470.1.

Example 90: N-(2-(((2-(2-(2-Hydroxyethoxy)ethoxy)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR130)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-(2-(2-aminoethoxy)ethoxy)ethanol (109 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→20:1→15:1) afforded compound (ZDR130) as a pale orange solid (81 mg, 0.15 mmol, 57%). ¹H NMR (300 MHz, CDCl₃) δ 2.90 (2H, t, J=5.0 Hz), 3.63 (2H, t, J=5.0 Hz), 3.69-3.78 (8H, m), 4.14 (2H, s), 6.44 (1H, br s), 7.33 (1H, d, J=8.4 Hz), 7.37-7.48 (2H, m), 7.54 (2H, d, J=8.3 Hz), 7.85 (1H, dd, J=7.1 and 1.7 Hz), 7.97-8.03 (3H, m); ESI-MS: m/z calcd for C₂₃H₂₆F₃N₃O₅S: 513.2; found [M+H]⁺: 514.2.

Example 91: N-(2-(((2-(2-Methoxyethoxy)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR131)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-(2-methoxyethoxy)ethanamine (97 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→30:1→20:1) afforded compound (ZDR131) as a pale yellow solid (80 mg, 0.16 mmol, 61%). ¹H NMR (300 MHz, CDCl₃) δ 2.95 (2H, t, J=5.1 Hz), 3.35 (3H, s), 3.59 (2H, t, J=5.1 Hz), 3.66-3.76 (4H, m), 4.16 (2H, s), 7.37-7.48 (3H, m), 7.56 (2H, d, J=8.3 Hz), 7.83 (1H, dd, J=7.3 and 1.5 Hz), 8.00 (2H, d, J=8.3 Hz), 8.03 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₂H₂₄F₃N₃O₄S: 483.1; found [M+H]⁺: 484.2.

Example 92: N-(2-(5,8,11-Trioxa-2-azadodecyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR132)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (128 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→30:1→20:1) afforded compound (ZDR132) as a pale orange solid (75 mg, 0.14 mmol, 53%). ¹H NMR (300 MHz, CDCl₃) δ 2.92 (2H, t, J=5.1 Hz), 3.29 (3H, s), 3.48-3.51 (2H, m), 3.62-3.65 (2H, m), 3.69-3.72 (6H, m), 4.13 (2H, s), 7.37-7.48 (3H, m), 7.55 (2H, d, J=8.2 Hz), 7.82 (1H, dd, J=7.2 and 1.5 Hz), 7.97 (2H, d, J=8.2 Hz), 8.03 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₄H₂₈F₃N₃O₅S: 527.2; found [M+H]⁺: 528.2.

Example 93: N-(2-(((2-Methoxyethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR133)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-methoxyethylamine (67 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→20:1→15:1) afforded compound (ZDR133) as a pale yellow solid (69 mg, 0.15 mmol, 57%). ¹H NMR (300 MHz, CDCl₃) δ 2.91 (2H, t, J=5.1 Hz), 3.46 (3H, s), 3.61 (2H, t, J=5.1 Hz), 4.14 (2H, s), 7.36 (1H, d, J=8.4 Hz), 7.40-7.50 (2H, m), 7.57 (2H, d, J=8.3 Hz), 7.87 (1H, dd, J=7.3 and 1.5 Hz), 7.98 (2H, d, J=8.3 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₀F₃N₃O₃S: 439.1; found [M+H]⁺: 440.1.

Example 94: N-(2-((tert-Butylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR135)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), tert-butylamine (81 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→30:1→20:1) afforded compound (ZDR135) as a pale orange solid (75 mg, 0.17 mmol, 65%). ¹H NMR (300 MHz, CDCl₃) δ 1.24 (9H, s), 4.13 (2H, s), 7.35-7.43 (3H, m), 7.57 (2H, d, J=8.3 Hz), 7.78 (1H, dd, J=7.0 and 1.8 Hz), 7.98 (1H, d, J=8.5 Hz), 8.02 (2H, d, J=8.3 Hz); ESI-MS: m/z calcd for C₂₁H₂₂F₃N₃O₂S: 437.1; found [M+H]⁺: 438.1.

Example 95: N-(2-((Diisopropylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR136)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), diisopropylamine (109 μL, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→30:1→20:1) afforded compound (ZDR136) as a white solid (40 mg, 0.08 mmol, 30%). ¹H NMR (300 MHz, CDCl₃) δ 1.03 (12H, d, J=6.5 Hz), 2.96-3.08 (2H, m), 3.86 (2H, s), 7.36-7.49 (2H, m), 7.58 (2H, d, J=8.3 Hz), 7.76-7.82 (2H, m), 7.98-8.03 (3H, m); ESI-MS: m/z calcd for C₂₃H₂₆F₃N₃O₂S: 465.2; found [M+H]⁺: 466.2.

Example 96: (E)-N-(2-(((Benzyloxy)imino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR137)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol), benzyloxyamine hydrochloride (41 mg, 0.26 mmol) and sodium acetate (43 mg, 0.52 mmol) in ethanol (10 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR137) as a white solid (75 mg, 0.15 mmol, 57%). ¹H NMR (400 MHz, d₆-acetone) δ 5.32 (2H, s), 7.34-7.47 (3H, m), 7.49 (2H, d, J=8.4 Hz), 7.57 (1H, t, J=7.9 Hz), 7.67 (1H, dd, J=8.4 and 1.2 Hz), 7.81 (2H, d, J=8.4 Hz), 7.90 (1H, dd, J=7.6 and 1.2 Hz), 7.98 (1H, d, J=7.6 Hz), 8.15 (2H, d, J=8.4 Hz), 8.30 (1H, d, J=8.4 Hz), 8.36 (1H, s), 9.59 (1H, s); ESI-MS: m/z calcd for C₂₄H₁₈F₃N₃O₃S: 485.1; found [M+Na]⁺: 508.1.

Example 97: (E)-N-(2-((2-Benzylhydrazineylidene)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR138)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol), benzylhydrazine dihydrochloride (50 mg, 0.26 mmol) and sodium acetate (43 mg, 0.52 mmol) in ethanol (10 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR138) as a yellow solid (70 mg, 0.14 mmol, 53%). ¹H NMR (400 MHz, CDCl₃) δ 4.56 (2H, d, J=4.6 Hz), 6.28 (1H, t, J=4.6 Hz), 7.34-7.45 (7H, m), 7.59 (2H, d, J=8.4 Hz), 7.70 (1H, s), 7.77 (1H, dd, J=7.7 and 1.3 Hz), 7.98-8.00 (4H, m); ESI-MS: m/z calcd for C₂₄H₁₉F₃N₄O₂S: 484.1; found [M+H]⁺: 485.1.

Example 98: N-(2-(((N,N′-Bis-Boc-2-Guanidinoethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR139)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), compound (ZDR140) (235 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→30:1→20:1) afforded compound (ZDR139) as a pale yellow solid (120 mg, 0.17 mmol, 65%). ¹H NMR (300 MHz, CDCl₃) δ 1.45 (9H, s), 1.48 (9H, s), 2.86 (2H, t, J=5.9 Hz), 3.52-3.58 (2H, m), 4.07 (2H, s), 7.35-7.46 (2H, m), 7.55-7.59 (3H, m), 7.79 (1H, dd, J=7.3 and 1.4 Hz), 7.98 (2H, d, J=8.3 Hz), 8.02 (1H, d, J=8.4 Hz), 8.70-8.73 (1H, m), 11.49 (1H, br s).

Example 99: 1-(2-Aminoethyl)-N,N′-Bis-Boc-guanidine—Compound (ZDR140)

A solution of N,N′-Bis-Boc-1-guanylpyrazol (1.0 g, 3.22 mmol) in dichloromethane (10 mL) was added dropwise to a solution of 1,2-diaminoethane (2.1 mL, 32.2 mmol) in dichloromethane (10 mL), and the mixture stirred at room temperature for 18 h. The mixture was then washed with water (5×20 mL) and the separated organic layer dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (ethyl acetate) afforded compound (ZDR140) as an off-white solid (800 mg, 2.64 mmol, 81%). ¹H NMR (300 MHz, CDCl₃) δ 1.48 (18H, s), 2.88 (2H, t, J=5.9 Hz), 3.44-3.50 (2H, m), 8.63 (1H, br s).

Example 100: tert-Butyl (E)-(2-(2-nitroguanidino)ethyl)carbamate—Compound (ZDR141)

A solution of N-Boc-ethylenediamine (1.0 g, 6.24 mmol) and N-nitro-S-methylisothiourea (0.84 g, 6.24 mmol) in ethanol (30 mL) was heated at 60° C. for 18 h. The solvent was then removed in vacuo to afford compound (ZDR141) as a white solid (1.5 g), which was used without further purification. ¹H NMR (300 MHz, d₆-DMSO) δ 1.37 (9H, s), 3.06-3.10 (2H, m), 3.17-3.21 (2H, m), 6.86-6.88 (1H, m).

Example 101: (E)-1-(2-Aminoethyl)-2-nitroguanidine trifluoroacetate—Compound (ZDR142)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR141) (192 mg, 0.78 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR142) as a colourless oil (190 mg, 0.78 mmol, quant.), which was used without further purification.

Example 102: N-(2-(((2-Guanidinoethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide di-trifluoroacetate—Compound (ZDR143)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR139) (100 mg, 0.14 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR143) as a white solid (92 mg, 0.14 mmol, quant.), which was used without further purification. ¹H NMR (300 MHz, d₄-MeOH) δ 3.48 (2H, t, J=6.2 Hz), 3.77 (2H, t, J=6.2 Hz), 4.68 (2H, s), 7.48-7.56 (2H, m), 7.61 (1H, dd, J=8.3 and 1.1 Hz), 7.77 (2H, d, J=8.3 Hz), 7.83 (1H, dd, J=7.7 and 1.1 Hz), 8.15 (2H, d, J=8.3 Hz), 8.33 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₁F₃N₆O₂S: 466.1; found [M+H]⁺: N/A.

Example 103: (E)-N-(2-(((2-(2-Nitroguanidino)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR145)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), compound (ZDR142) (190 mg, ca. 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→30:1→20:1) afforded compound (ZDR145) as a white solid (80 mg, 0.15 mmol, 57%). ¹H NMR (300 MHz, d₆-DMSO) δ 2.71 (2H, t, J=5.8 Hz), 3.31 (2H, t, J=5.8 Hz), 3.95 (2H, s), 7.45-7.53 (2H, m), 7.63-7.73 (2H, m), 7.79 (2H, d, J=8.3 Hz), 8.01 (2H, d, J=8.3 Hz), 8.24 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₀F₃N₇O₄S: 511.1; found [M+H]⁺: 512.2.

Example 104: tert-Butyl (2-acetamidoethyl)carbamate—Compound (ZDR146)

A solution of N-Boc-ethylenediamine (1.0 g, 6.24 mmol), acetyl chloride (443 μL, 6.24 mmol) and triethylamine (2.6 mL, 18.7 mmol) in dichloromethane (30 mL) was stirred at room temperature for 18 h. The mixture was then washed with water (2×20 mL) and the separated organic layer dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane) afforded compound (ZDR146) as a white solid (900 mg, 4.44 mmol, 71%). ¹H NMR (300 MHz, CDCl₃) δ 1.29 (9H, s) 1.84 (3H, s), 3.07-3.15 (2H, m), 3.16-3.23 (2H, m), 5.57 (1H, t, J=5.3 Hz), 7.11 (1H, t, J=5.3 Hz).

Example 105: N-(2-Aminoethyl)acetamide trifluoroacetate—Compound (ZDR147)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR146) (157 mg, 0.78 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR147) as a colourless oil (150 mg, 0.78 mmol, quant.), which was used without further purification.

Example 106: N-(2-(((8-((4-(Trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)amino)ethyl)acetamide—Compound (ZDR148)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), compound (ZDR147) (150 mg, ca. 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1→30:1→20:1) afforded compound (ZDR148) as a pale yellow solid (80 mg, 0.17 mmol, 65%). ¹H NMR (300 MHz, CDCl₃) δ 1.99 (3H, s), 2.92 (2H, t, J=6.1 Hz), 3.44-3.49 (2H, m), 4.11 (2H, s), 7.38-7.47 (3H, m), 7.54 (2H, d, J=8.3 Hz), 7.77 (1H, dd, J=7.5 and 1.4 Hz), 7.98 (2H, d, J=8.3 Hz), 8.04 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₁H₂₁F₃N₄O₃S: 466.1; found [M+H]⁺: 467.1.

Example 107: (E)-N-(2-((2-Methylhydrazineylidene)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR153)

A similar procedure to that described for the preparation of compound (ZDR118) was followed using compound (ZDR019) (100 mg, 0.26 mmol), methylhydrazine dihydrochloride (21 mg, 0.26 mmol) and sodium acetate (43 mg, 0.52 mmol) in ethanol (10 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR153) as a yellow solid (72 mg, 0.17 mmol, 65%). ¹H NMR (300 MHz, CDCl₃) δ 3.10 (3H, s), 7.32-7.43 (2H, m), 7.61-7.63 (3H, m), 7.76 (1H, dd, J=7.6 and 1.3 Hz), 7.92-8.03 (4H, m); ESI-MS: m/z calcd for C₁₈H₁₅F₃N₄O₂S: 408.1; found [M+H]⁺: 409.1.

Example 108: N-(2-((Dimethylamino)methyl)quinolin-8-yl)benzene-1,4-disulfonamide—Compound (ZDR154)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-(aminosulfonyl)benzenesulfonyl chloride (125 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→15:1→10:1) afforded compound (ZDR154) as a pale yellow solid (50 mg, 0.11 mmol, 25%). ¹H NMR (300 MHz, CDCl₃/d₄-MeOH, 1:1) δ 2.34 (6H, s), 3.75 (2H, s), 4.51 (2H, br s), 7.32 (1H, d, J=8.3 Hz), 7.37-7.41 (1H, m), 7.48 (1H, dd, J=7.4 and 1.2 Hz), 7.83-7.86 (3H, m), 7.99 (2H, 8.5 Hz), 8.07 (1H, d, J=8.3 Hz); ESI-MS: m/z calcd for C₁₈H₂₀N₄O₄S₂: 420.1; found [M+H]⁺: 421.1.

Example 109: N-(2-((Dimethylamino)methyl)quinolin-8-yl)benzene-1,3-disulfonamide—Compound (ZDR155)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 3-(aminosulfonyl)benzenesulfonyl chloride (125 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→15:1→10:1) afforded compound (ZDR155) as a pale yellow solid (57 mg, 0.13 mmol, 29%). ¹H NMR (300 MHz, CDCl₃/d₄-MeOH, 1:1) δ 2.38 (6H, s), 3.81 (2H, s), 4.53 (2H, br s), 7.32 (1H, d, J=8.4 Hz), 7.39-7.51 (3H, m), 7.87 (1H, dd, J=7.4 and 1.3 Hz), 7.91-7.94 (1H, m), 7.95-7.99 (1H, m), 8.08 (1H, d, J=8.4 Hz), 8.49-8.50 (1H, m); ESI-MS: m/z calcd for C₁₈H₂₀N₄O₄S₂: 420.1; found [M+H]⁺: 421.1.

Example 110: 4-Amino-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR160)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR333) (60 mg, 0.13 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v). The residue was then taken up in dichloromethane (10 mL), diluted with water and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 30:1→20:1) afforded compound (ZDR160) as a white solid (40 mg, 0.11 mmol, 84%). ¹H NMR (300 MHz, CDCl₃) δ 2.29 (6H, s), 3.71 (2H, s), 4.02 (2H, br s), 6.47 (2H, d, J=8.6 Hz), 7.34-7.42 (2H, m), 7.56 (1H, d, J=8.4 Hz), 7.64 (2H, d, J=8.6 Hz), 7.74 (1H, dd, J=6.7 and 2.2 Hz), 8.03 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₂₀N₄O₂S: 356.1; found [M+H]⁺: 357.1.

Example 111: 3-Amino-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR162)

A suspension of compound (ZR313) (60 mg, 0.15 mmol) and palladium-on-carbon (cat., 10% w/w) in methanol (10 mL) was stirred at room temperature under an atmosphere of hydrogen for 18 h. The mixture was then filtered through a pad of Celite® and the solvent removed in vacuo. Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR162) as a pale yellow solid (45 mg, 0.12 mmol, 80%). ¹H NMR (300 MHz, CDCl₃) δ 2.31 (6H, s), 3.74 (2H, s), 3.78 (2H, br s), 6.64-6.70 (1H, m), 7.07 (1H, t, J=7.8 Hz), 7.18-7.21 (2H, m), 7.36-7.46 (2H, m), 7.56 (1H, d, J=8.4 Hz), 7.77 (1H, dd, J=7.0 and 1.8 Hz), 8.05 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₂₀N₄O₂S: 356.1; found [M+H]⁺: 357.1.

Example 112: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3-hydroxybenzenesulfonamide—Compound (ZDR163)

A solution of compound (ZDR314) (75 mg, 0.20 mmol) and boron tribromide (400 μL, 0.40 mmol, 1 M in dichloromethane) in dichloromethane (2 mL) was stirred at room temperature for 2 h. The mixture was then diluted with dichloromethane/methanol (25 mL, 9:1 v/v), water (25 mL) added and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 30:1→20:1→15:1) afforded compound (ZDR163) as a beige solid (45 mg, 0.12 mmol, 60%). ¹H NMR (300 MHz, CDCl₃/d₄-MeOH, 3:1 v/v) δ 2.31 (6H, s), 3.74 (2H, s), 6.80-6.83 (1H, m), 7.08 (1H, t, J=7.9 Hz), 7.27-7.40 (5H, m), 7.76 (1H, dd, J=7.4 and 1.4 Hz), 8.01 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₉N₃O₃S: 357.1; found [M+H]⁺: 358.1.

Example 113: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-hydroxybenzenesulfonamide—Compound (ZDR164)

A similar procedure to that described for the preparation of compound (ZDR163) was followed using compound (ZDR063) (75 mg, 0.20 mmol) and boron tribromide (400 μL, 0.40 mmol, 1 M in dichloromethane) in dichloromethane (2 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→15:1) afforded compound (ZDR164) as a white solid (53 mg, 0.14 mmol, 70%). ¹H NMR (400 MHz, CDCl₃) δ 2.35 (6H, s), 3.76 (2H, s), 6.49 (2H, d, J=8.8 Hz), 7.41-7.42 (2H, m), 7.45 (1H, d, J=8.4 Hz), 7.54 (2H, d, J=8.8 Hz), 7.85 (1H, dd, J=7.4 and 1.4 Hz), 8.01 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₉N₃O₃S: 357.1; found [M+H]⁺: 358.1.

Example 114: N-(2-(((3,5-Dichloro-2-hydroxyphenyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR167)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-amino-4,6-dichlorophenol (138 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1) afforded compound (ZDR167) as an orange solid (55 mg, 0.10 mmol, 38%). ¹H NMR (300 MHz, CDCl₃) δ 4.63 (2H, s), 5.57 (1H, br s), 6.54 (1H, d, J=2.3 Hz), 6.71 (1H, d, J=2.3 Hz), 7.37-7.49 (3H, m), 7.56 (2H, d, J=8.3 Hz), 7.80 (1H, dd, J=7.3 and 1.4 Hz), 7.94 (2H, d, J=8.3 Hz), 8.07 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₃H₁₆Cl₂F₃N₃O₃S: 541.0; found [M+H]⁺: 541.9.

Example 115: N-(2-(((2-Hydroxy-5-nitrophenyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR170)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-amino-4-nitrophenol (120 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1) afforded compound (ZDR170) as an orange solid (25 mg, 0.04 mmol, 15%). ¹H NMR (300 MHz, CDCl₃) δ 4.77 (2H, s), 6.89-6.93 (1H, m), 7.38-7.43 (2H, m), 7.49 (1H, dd, J=8.2 and 1.3 Hz), 7.56 (2H, d, J=8.3 Hz), 7.59-7.63 (2H, m), 7.73 (1H, dd, J=7.5 and 1.3 Hz), 7.90 (2H, d, J=8.3 Hz), 8.09 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₃H₁₇F₃N₄O₅S: 518.1; found [M+Na]⁺:541.1.

Example 116: N-(2-(((2-Hydroxyphenyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR171)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), 2-aminophenol (85 mg, 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1) afforded compound (ZDR171) as an orange solid (38 mg, 0.08 mmol, 30%). ¹H NMR (300 MHz, CDCl₃) δ 4.73 (2H, s), 6.61-6.66 (1H, m), 6.74-6.85 (3H, m), 7.37 (2H, d, J=8.3 Hz), 7.44 (1H, dd, J=8.3 and 1.1 Hz), 7.48 (2H, d, J=8.3 Hz), 7.75 (1H, dd, J=7.4 and 1.1 Hz), 7.84 (2H, d, J=8.3 Hz), 8.02 (1H, d, J=8.3 Hz); ESI-MS: m/z calcd for C₂₃H₁₈F₃N₃O₃S: 473.1; found [M+H]⁺: 474.1.

Example 117: tert-Butyl (2-(methylsulfonamido)ethyl)carbamate—Compound (ZDR173)

A similar procedure to that described for the preparation of compound (ZDR146) was followed using N-Boc-ethylenediamine (1.0 g, 6.24 mmol), methanesulfonyl chloride (482 μL, 6.24 mmol) and triethylamine (2.6 mL, 18.7 mmol) in dichloromethane (30 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR173) as a white solid (1.20 g, 5.03 mmol, 80%). ¹H NMR (300 MHz, CDCl₃/d₄-MeOH, 1:1 v/v) δ 1.41 (9H, s), 2.93 (3H, s), 3.11-3.23 (4H, m).

Example 118: tert-Butyl (2-(phenylsulfonamido)ethyl)carbamate—Compound (ZDR174)

A similar procedure to that described for the preparation of compound (ZDR146) was followed using N-Boc-ethylenediamine (1.0 g, 6.24 mmol), benzenesulfonyl chloride (796 μL, 6.24 mmol) and triethylamine (2.6 mL, 18.7 mmol) in dichloromethane (30 mL). Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound (ZDR174) as a white solid (1.70 g, 5.65 mmol, 90%). ¹H NMR (300 MHz, CDCl₃/d₄-MeOH, 1:1 v/v) δ 1.38 (9H, s), 2.96 (2H, t, J=6.1 Hz), 3.11-3.18 (2H, m), 7.45-7.57 (3H, m), 7.80-7.85 (2H, m).

Example 119: N-(2-Aminoethyl)benzenesulfonamide trifluoroacetate—Compound (ZDR178)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR174) (234 mg, 0.78 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR178) as a colourless oil (230 mg, 0.78 mmol, quant.), which was used without further purification.

Example 120: N-(2-Aminoethyl)methanesulfonamide trifluoroacetate—Compound (ZDR179)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR173) (157 mg, 0.78 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR179) as a colourless oil (185 mg, 0.78 mmol, quant.), which was used without further purification.

Example 121: N-(2-(Hydroxymethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR176)

A suspension of compound (ZDR019) (100 mg, 0.26 mmol) and sodium borohydride (14 mg, 0.39 mmol) in ethanol (5 mL) was stirred at room temperature for 18 h. The mixture was then diluted with dichloromethane (25 mL), water (25 mL) added and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 50:1) afforded compound (ZDR176) as a white solid (80 mg, 0.20 mmol, 76%). ¹H NMR (300 MHz, CDCl₃) δ 4.96 (2H, s), 7.37 (1H, d, J=8.4 Hz), 7.43-7.54 (2H, m), 7.58 (2H, d, J=8.3 Hz), 7.89 (1H, dd, J=7.4 and 1.4 Hz), 8.02 (2H, d, J=8.3 Hz), 8.09 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₇H₁₃F₃N₂O₃S: 382.1; found [M+Na]⁺: 405.0.

Example 122: N-(2-(((2-(Methylsulfonamido)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR180)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), compound (ZDR179) (180 mg, ca. 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR180) as a pale yellow solid (63 mg, 0.12 mmol, 46%). ¹H NMR (300 MHz, CDCl₃) δ 2.97-3.00 (2H, m), 2.99 (3H, s), 3.34-3.37 (2H, m), 3.98 (2H, s), 7.35 (1H, d, J=8.4 Hz), 7.38 (1H, d, J=7.4 Hz), 7.41 (1H, dd, J=8.3 and 1.4 Hz), 7.48 (2H, d, J=8.3 Hz), 7.74 (1H, dd, J=7.4 and 1.4 Hz), 7.97-8.01 (3H, m); ESI-MS: m/z calcd for C₂₀H₂₁F₃N₄O₄S₂: 502.1; found [M+H]⁺: 503.1.

Example 123: N-(2-(((2-(Phenylsulfonamido)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR181)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), compound (ZDR178) (230 mg, ca. 0.78 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in 1,2-dichloroethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR181) as a pale yellow solid (59 mg, 0.10 mmol, 38%). ¹H NMR (300 MHz, CDCl₃) δ 2.81-2.85 (2H, m), 3.10-3.14 (2H, m), 3.97 (2H, s), 7.36-7.54 (6H, m), 7.57 (2H, d, J=8.3 Hz), 7.77 (1H, dd, J=7.1 and 1.6 Hz), 7.85-7.88 (2H, m), 8.01-8.04 (3H, m); ESI-MS: m/z calcd for C₂₅H₂₃F₃N₄O₄S₂: 564.1; found [M+H]⁺: 565.1.

Example 124: N-(2-(Aminomethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR184)

A similar procedure to that described for the preparation of compound (ZDR162) was followed using compound (ZDR126) (100 mg, 0.25 mmol) and palladium-on-carbon (cat., 10% w/w) in methanol (20 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR184) as a yellow solid (64 mg, 0.16 mmol, 64%). ¹H NMR (400 MHz, d₆-DMSO): δ 4.40 (2H, s), 6.84 (2H, br s), 7.38 (1H, d, J=7.8 Hz), 7.45 (1H, d, J=7.8 Hz), 7.54 (1H, d, J=8.5 Hz), 7.59 (1H, d, J=7.4 Hz), 7.70 (2H, d, J=8.2 Hz), 8.00 (2H, d, J=8.2 Hz), 8.25 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₇H₁₄F₃N₃O₂S: 381.1; found [M+H]⁺: 382.0.

Example 125: N-((8-((4-(Trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)acetamide—Compound (ZDR185)

A solution of compound (ZDR184) (50 mg, 0.13 mmol) and acetyl chloride (10 μL, 0.14 mmol) in dichloromethane (3 mL) was stirred at room temperature for 18 h. The mixture was then diluted with dichloromethane (25 mL), water (25 mL) added and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR185) as a colourless solid (30 mg, 0.07 mmol, 53%). ¹H NMR (400 MHz, CDCl₃): δ 2.14 (3H, s), 4.70 (2H, d, J=5.6 Hz), 6.78 (1H, br s), 7.38-7.43 (2H, m), 7.47 (1H, dd, J=8.3 and 1.3 Hz), 7.60 (2H, d, J=8.4 Hz), 7.89 (1H, dd, J=7.5 and 1.3 Hz), 8.01 (2H, d, J=8.4 Hz), 8.05 (1H, d, J=8.5 Hz), 9.29 (1H, br s); ESI-MS: m/z calcd for C₁₉H₁₆F₃N₃O₃S: 423.1; found [M+Na]⁺: 446.1.

Example 126: N-(2-(N,N′-Bis-Boc-Guanidinomethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR186)

A solution of compound (ZDR184) (55 mg, 0.14 mmol) and N,N′-di-Boc-1H-pyrazole-1-carboxamidine (54 mg, 0.17 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 18 h. The mixture was then diluted with ethyl acetate (10 mL), water (25 mL) added and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (petroleum ether/ethyl acetate, 4:1) afforded compound (ZDR186) as a colourless solid (80 mg, 0.12 mmol, 85%). ¹H NMR (400 MHz, CDCl₃): δ 1.54 (9H, s), 1.63 (9H, s), 4.88 (2H, d, J=3.9 Hz), 7.28 (1H, d, J=8.4 Hz), 7.44-7.56 (4H, m), 7.96-8.01 (3H, m), 8.07 (1H, d, J=8.4 Hz), 9.13 (1H, br s), 10.12 (1H, br s), 11.58 (1H, br s).

Example 127: N-(2-(Guanidinomethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide trifluoroacetate—Compound (ZDR187)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR186) (80 mg, 0.13 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR187) as a white solid (67 mg, 0.13 mmol, quant.), which was used without further purification. ¹H NMR (400 MHz, d₄-MeOH): δ 4.66 (2H, s), 7.43 (1H, d, J=8.5 Hz), 7.51 (1H, t, J=8.0 Hz), 7.63-7.67 (3H, m), 7.88 (1H, dd, J=7.6 and 1.0 Hz), 7.98 (2H, d, J=8.4 Hz), 8.25 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₈H₁₆F₃N₅O₂S: 423.1; found [M+H]⁺: 424.0.

Example 128: (E)-N-(2-((2-Nitroguanidino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR188)

A solution of compound (ZDR184) (50 mg, 0.13 mmol) and N-nitro-S-methylisothiourea (21 mg, 0.16 mmol) in ethanol (2 mL) was stirred at 40° C. for 3 days, and the solvent then removed in vacuo. Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR188) as a pale yellow solid (43 mg, 0.09 mmol, 69%). ¹H NMR (400 MHz, d₆-DMSO): δ 4.65 (2H, d, J=4.4 Hz), 7.48 (1H, d, J=8.5 Hz), 7.57 (1H, t, J=7.9 Hz), 7.74 (1H, d, J=8.4 Hz), 7.77 (2H, d, J=8.4 Hz), 7.82 (1H, d, J=7.6 Hz), 8.01 (2H, d, J=8.4 Hz), 8.34 (1H, d, J=8.5 Hz), 9.16 (1H, br s); ESI-MS: m/z calcd for C₁₈H₁₈F₃N₆O₄S: 468.1; found [M+Na]⁺: 491.1.

Example 129: 2-Chloro-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR190)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 2-chlorobenzenesulfonyl chloride (66 μL, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR190) as a tan solid (80 mg, 0.21 mmol, 47%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.75 (2H, s), 7.29-7.41 (5H, m), 7.63 (1H, d, J=8.5 Hz), 7.71 (1H, d, J=7.4 Hz), 8.05 (1H, d, J=8.5 Hz), 8.18 (1H, d, J=7.8 Hz); ESI-MS: m/z calcd for C₁₈H₁₈ClN₃O₂S: 375.1; found [M+H]⁺: 376.1.

Example 130: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-2-(trifluoromethoxy)benzenesulfonamide—Compound (ZDR191)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 2-(trifluoromethoxy)benzenesulfonyl chloride (117 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR191) as a pale yellow solid (71 mg, 0.17 mmol, 38%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.74 (2H, s), 7.21 (1H, d, J=8.0 Hz), 7.26-7.35 (2H, m), 7.41 (1H, d, J=8.0 Hz), 7.48 (1H, t, J=7.5 Hz), 7.66 (1H, d, J=8.4 Hz), 7.73 (1H, d, J=7.5 Hz), 8.06 (1H, d, J=8.4 Hz), 8.13 (1H, d, J=7.7 Hz); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₃S: 425.1; found [M+H]⁺: 426.1.

Example 131: N-(2-((Dimethylamino)methyl)quinolin-8-yl)morpholine-4-sulfonamide—Compound (ZDR192)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), morpholine-4-sulfonyl chloride (90 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1→10:1) afforded compound (ZDR192) as a pale yellow solid (33 mg, 0.09 mmol, 20%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.24 (4H, t, J=4.7 Hz), 3.58 (4H, t, J=4.7 Hz), 3.75 (2H, s), 7.45 (1H, t, J=7.8 Hz), 7.50 (1H, dt, J=8.2 and 1.5 Hz), 7.67 (1H, d, J=8.5 Hz), 7.83 (1H, dd, J=7.3 and 1.5 Hz), 8.14 (1H, d, J=8.5 Hz), 8.98 (1H, brs); ESI-MS: m/z calcd for C₁₆H₂₂N₄O₃S: 350.1; found [M+H]⁺: 351.1.

Example 132: N-(2-((Dimethylamino)methyl)quinolin-8-yl)piperidine-1-sulfonamide—Compound (ZDR193)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), piperidine-1-sulfonyl chloride (68 μL, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1→10:1) afforded compound (ZDR193) as a yellow oil (35 mg, 0.10 mmol, 22%). ¹H NMR (400 MHz, CDCl₃) δ 1.37-1.42 (2H, m), 1.46-1.51 (4H, m), 2.32 (6H, s), 3.25 (4H, t, J=5.5 Hz), 3.74 (2H, s), 7.42-7.48 (2H, m), 7.65 (1H, d, J=8.5 Hz), 7.73 (1H, dd, J=6.8 and 2.0 Hz), 8.12 (1H, d, J=8.5 Hz), 8.95 (1H, brs); ESI-MS: m/z calcd for C₁₇H₂₄N₄O₂S: 348.2; found [M+H]⁺: 349.2.

Example 133: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-1-methyl-1H-pyrazole-4-sulfonamide—Compound (ZDR194)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 1-methyl-1H-pyrazole-4-sulfonyl chloride (88 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→8:1) afforded compound (ZDR194) as a pale yellow solid (14 mg, 0.04 mmol, 9%). ¹H NMR (400 MHz, CDCl₃) δ 2.31 (6H, s), 3.72 (2H, s), 3.77 (3H, s), 7.42-7.49 (2H, m), 7.61 (1H, d, J=8.5 Hz), 7.70 (1H, s), 7.75 (1H, s), 7.82 (1H, dd, J=7.5 and 1.5 Hz), 8.09 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₆H₁₉N₅O₂S: 345.1; found [M+Na]⁺: 368.1.

Example 134: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-1-methyl-1H-imidazole-4-sulfonamide—Compound (ZDR195)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 1-methyl-1H-imidazole-4-sulfonyl chloride (88 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→7:1) afforded compound (ZDR195) as a yellow solid (44 mg, 0.12 mmol, 27%). ¹H NMR (400 MHz, CDCl₃) δ 2.33 (6H, s), 3.64 (3H, s), 3.76 (2H, s), 7.32-7.42 (3H, m), 7.54-7.60 (2H, m), 7.78-7.84 (1H, m), 8.05 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₆H₁₉N₅O₂S: 345.1; found [M+H]⁺: 346.1.

Example 135: N-(2-((Dimethylamino)methyl)quinolin-8-yl)benzo[c][1,2,5]thiadiazole-4-sulfonamide—Compound (ZDR196)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 2,1,3-benzothiadiazole-4-sulfonyl chloride (114 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR196) as a pale yellow solid (145 mg, 0.36 mmol, 81%). ¹H NMR (400 MHz, CDCl₃) δ 2.31 (6H, s), 3.70 (2H, s), 7.31-7.37 (2H, m), 7.54 (1H, d, J=8.5 Hz), 7.61 (1H, dd, J=8.9 and 6.9 Hz), 7.84 (1H, dd, J=7.0 and 1.9 Hz), 7.97 (1H, d, J=8.5 Hz), 8.08 (1H, dd, J=8.9 and 0.9 Hz), 8.33 (1H, dd, J=6.9 and 0.9 Hz); ESI-MS: m/z calcd for C₁₈H₁₇N₅O₂S₂: 399.1; found [M+H]⁺: 400.1.

Example 136: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-2-fluorobenzenesulfonamide—Compound (ZDR201)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 2-fluorobenzenesulfonyl chloride (64 μL, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR201) as a pale yellow solid (72 mg, 0.20 mmol, 45%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.76 (2H, s), 6.97-7.02 (1H, m), 7.13-7.17 (1H, m), 7.35 (1H, t, J=7.7 Hz), 7.39-7.45 (2H, m), 7.61 (1H, d, J=8.5 Hz), 7.75 (1H, dd, J=7.5 and 1.2 Hz), 7.93-7.98 (1H, m), 8.05 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₈H₁₈FN₃O₂S: 359.1; found [M+H]⁺: 360.1.

Example 137: 2-Bromo-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR202)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 2-bromobenzenesulfonyl chloride (125 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR202) as a pale yellow solid (57 mg, 0.14 mmol, 31%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.76 (2H, s), 7.25-7.41 (4H, m), 7.55 (1H, d, J=7.8 Hz), 7.63 (1H, d, J=8.5 Hz), 7.71 (1H, d, J=7.4 Hz), 8.05 (1H, d, J=8.5 Hz), 8.24 (1H, d, J=7.5 Hz); ESI-MS: m/z calcd for C₁₈H₁₈BrN₃O₂S: 419.0; found [M+H]⁺: 420.0.

Example 138: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-2,4-dimethylthiazole-5-sulfonamide—Compound (ZDR203)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride (103 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR203) as a pale yellow solid (40 mg, 0.11 mmol, 25%). ¹H NMR (400 MHz, CDCl₃) δ 2.31 (6H, s), 2.51 (3H, s), 2.55 (3H, s), 3.72 (2H, s), 7.44 (1H, t, J=7.7 Hz), 7.52 (1H, d, J=8.0 Hz), 7.64 (1H, d, J=8.5 Hz), 7.85 (1H, d, J=7.4 Hz), 8.10 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₇H₂₀N₄O₂S₂: 376.1; found [M+H]⁺: 377.1.

Example 139: N-(2-((Dimethylamino)methyl)quinolin-8-yl)pyrrolidine-1-sulfonamide—Compound (ZDR204)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), pyrrolidine-1-sulfonyl chloride (83 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 10:1→5:1) afforded compound (ZDR204) as a pale brown solid (17 mg, 0.05 mmol, 11%). ¹H NMR (400 MHz, CDCl₃) δ 1.72-1.75 (4H, m), 2.32 (6H, s), 3.34-3.37 (4H, m), 3.75 (2H, s), 7.43-7.48 (2H, m), 7.65 (1H, d, J=8.5 Hz), 7.76 (1H, dd, J=7.0 and 2.0 Hz), 8.12 (1H, d, J=8.5 Hz), 8.99 (1H, brs); ESI-MS: m/z calcd for C₁₆H₂₂N₄O₂S: 334.1; found [M+H]⁺: 335.2.

Example 140: 2-(Dimethylamino)-N-((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)acetamide—Compound (ZDR205)

A solution of compound (ZDR184) (50 mg, 0.13 mmol), N,N-dimethylglycine hydrochloride (21 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) and triethylamine (55 μL, 0.39 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 18 h. The mixture was then diluted with dichloromethane (25 mL), water (25 mL) added and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 50:1→30:1→15:1) afforded compound (ZDR205) as a pale yellow solid (30 mg, 0.06 mmol, 46%). ¹H NMR (300 MHz, CDCl₃) δ 2.46 (6H, s), 3.13 (2H, s), 4.77 (2H, d, J=5.4 Hz), 7.39 (1H, d, J=8.4 Hz), 7.45 (1H, d, J=7.3 Hz), 7.50 (1H, dd, J=8.4 and 1.3 Hz), 7.63 (2H, d, J=8.3 Hz), 7.84 (1H, dd, J=7.3 and 1.3 Hz), 8.03 (2H, d, J=8.3 Hz), 8.09 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₁H₂₁F₃N₄O₃S: 466.1; found [M+H]⁺: 467.1.

Example 141: N-(2-(Methylsulfonamidomethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR209)

A similar procedure to that described for the preparation of compound (ZDR185) was followed using compound (ZDR184) (50 mg, 0.13 mmol), methanesulfonyl chloride (11 μL, 0.15 mmol) and triethylamine (55 μL, 0.39 mmol) in dichloromethane (3 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR209) as a colourless solid (35 mg, 0.07 mmol, 53%). ¹H NMR (400 MHz, CDCl₃) δ 3.08 (3H, s), 4.65 (2H, d, J=5.8 Hz), 6.24-6.26 (1H, m), 7.38 (1H, d, J=8.5 Hz), 7.43 (1H, d, J=7.6 Hz), 7.48 (1H, dd, J=8.0 and 1.5 Hz), 7.61 (2H, d, J=8.5 Hz), 7.84 (1H, dd, J=7.5 and 1.5 Hz), 8.08 (3H, dd, J=8.5 and 2.1 Hz), 9.51 (1H, br s); ESI-MS: m/z calcd for C₁₈H₁₆F₃N₃O₄S₂: 459.1; found [M+Na]⁺: 482.0.

Example 142: N-(2-(Phenylsulfonamidomethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR210)

A similar procedure to that described for the preparation or compound (ZDR185) was followed using compound (ZDR184) (50 mg, 0.13 mmol), benzenesulfonyl chloride (26 mg, 0.15 mmol) and triethylamine (55 μL, 0.39 mmol) in dichloromethane (3 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR210) as a pale yellow solid (51 mg, 0.09 mmol, 69%). ¹H NMR (400 MHz, CDCl₃) δ 4.47 (2H, d, J=5.7 Hz), 6.24 (1H, brt, J=5.7 Hz), 7.32 (1H, d, J=8.4 Hz), 7.39-7.49 (5H, m), 7.57 (2H, d, J=8.4 Hz), 7.82 (1H, dd, J=7.1 and 1.7 Hz), 7.90-7.93 (2H, m), 8.00 (1H, d, J=8.4 Hz), 8.03 (2H, d, J=8.4 Hz), 9.28 (1H, brs); ESI-MS: m/z calcd for C₂₃H₁₈F₃N₃O₄S₂: 521.1; found [M+Na]⁺: 544.1.

Example 143: 4-(Dimethylamino)-N-((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)butanamide trifluoroacetate—Compound (ZDR211)

A solution of compound (ZDR184) (50 mg, 0.13 mmol), 4-(dimethylamino)butyric acid hydrochloride (25 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol) and triethylamine (55 μL, 0.39 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 18 h (no work-up). Purification by RP-HLPC (30% to 90% A/B gradient over 60 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR211) as a white solid (30 mg, 0.05 mmol, 38%). ¹H NMR (400 MHz, d₆-acetone) δ 2.18 (2H, quin, J=6.9 Hz), 2.69 (2H, t, J=6.9 Hz), 3.01 (6H, s), 3.36 (2H, t, J=6.9 Hz), 4.71 (2H, d, J=5.5 Hz), 7.50-7.54 (2H, m), 7.65 (1H, dd, J=8.4 and 1.4 Hz), 7.79 (2H, d, J=8.3 Hz), 8.36 (1H, dd, J=7.6 and 1.2 Hz), 8.12 (2H, d, J=8.3 Hz), 8.26 (1H, d, J=8.4 Hz), 8.42 (1H, brs), 9.66 (1H, brs); ESI-MS: m/z calcd for C₂₃H₂₅F₃N₄O₃S: 494.2; found [M+H]⁺:495.2.

Example 144: N-(3-(Dimethylamino)propyl)-8-((4-(trifluoromethyl)phenyl)sulfonamido)quinoline-2-carboxamide trifluoroacetate—Compound (ZDR224)

A solution of compound (ZDR271) (79 mg, 0.20 mmol), 3-(dimethylamino)-1-propylamine (27 μL, 0.22 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol) and triethylamine (84 μL, 0.6 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 h. Trifluoroacetic acid (5 mL) was added and the solution was stirred at room temperature for a further 3 h, and the solvent removed in vacuo. Purification by RP-HLPC (30% to 90% A/B gradient over 60 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR224) as a white solid (21 mg, 0.03 mmol, 15%). ¹H NMR (400 MHz, d₆-acetone) δ 2.20 (2H, quin, J=6.9 Hz), 3.02 (6H, s), 3.40 (2H, t, J=6.9 Hz), 3.61 (2H, t, J=6.9 Hz), 7.64 (1H, t, J=8.0 Hz), 7.75-7.79 (3H, m), 7.96 (1H, dd, J=7.7 and 1.2 Hz), 8.09 (2H, d, J=8.1 Hz), 8.22 (1H, d, J=8.5 Hz), 8.47 (1H, d, J=8.5 Hz), 9.60 (1H, brs), 10.12 (1H, brs); ESI-MS: m/z calcd for C₂₂H₂₃F₃N₄O₃S: 480.1; found [M+H]⁺: N/A.

Example 145: N-(tert-Butoxycarbonyl)-N-((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)glycine—Compound (ZDR227)

A solution of compound (ZDR043) (500 mg, 0.93 mmol), di-tert-butyl dicarbonate (212 mg, 1.11 mmol) and triethylamine (391 μL, 2.79 mmol) in dimethylformamide (12 mL) was stirred at room temperature for 18 h. The mixture was then diluted with dichloromethane (50 mL), washed with aqueous sodium hydrogen sulfate (50 mL, 1 M) and the separated organic layer dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 10:1) afforded compound (ZDR227) as a yellow oil (400 mg, 0.74 mmol, 79%). ¹H NMR (400 MHz, CDCl₃) δ 1.52 (9H, s), 3.95-4.07 (2H, m), 4.71-4.78 (2H, m), 7.39-7.49 (3H, m), 7.61-7.64 (2H, m), 7.82-7.87 (1H, m), 8.01-8.10 (3H, m), 9.23 (1H, brs).

Example 146: tert-Butyl (2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)carbamate—Compound (ZDR234)

A solution of compound (ZDR246) (100 mg, 0.15 mmol) and N,N-dimethylethylenediamine (49 μL, 0.45 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 h. The mixture was then diluted with dichloromethane (50 mL), water (25 mL) added and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1→5:1) afforded compound (ZDR234) as a pale yellow solid (28 mg, 0.04 mmol, 26%). ¹H NMR (400 MHz, d₆-acetone) δ 1.32 (4.5H, s), 1.50 (4.5H, s), 2.19 (6H, s), 2.37 (2H, brs), 3.30 (2H, brs), 3.96-4.06 (2H, m), 4.77-4.80 (2H, m), 7.15-7.24 (1H, m), 7.51 (1H, t, J=7.6 Hz), 7.55-7.59 (1H, m), 7.64 (1H, d, J=8.0 Hz), 7.83-7.91 (3H, m), 8.18-8.21 (2H, m), 8.28 (1H, brs).

Example 147: 2,5-Dioxopyrrolidin-1-yl N-(tert-butoxycarbonyl)-N-((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)glycinate—Compound (ZDR246)

A solution of compound (ZDR227) (750 mg, 1.39 mmol), N-hydroxysuccinimide (191 mg, 1.66 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (318 mg, 1.66 mmol) in dichloromethane-dimethylformamide (20 mL, 10:1 v/v) was stirred at room temperature for 18 h. The mixture was then diluted with dichloromethane (50 mL), water (25 mL) added and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR246) as a yellow oil (630 mg, 1.0 mmol, 71%). ¹H NMR (400 MHz, CDCl₃) δ 1.30 (4.5H, s) 1.51 (4.5H, s), 3.46 (4H, s), 4.30-4.43 (2H, m), 4.69-4.78 (2H, m), 7.39-7.48 (4H, m), 7.61 (2H, d, J=7.9 Hz), 7.84-7.86 (1H, m), 8.02-8.08 (2H, m), 9.29 (1H, brs).

Example 148: tert-Butyl(2-oxo-2-((2-(piperidin-1-yl)ethyl)amino)ethyl)((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)carbamate—Compound (ZDR247)

A similar procedure to that described for the preparation of compound (ZDR234) was followed using compound (ZDR246) (100 mg, 0.15 mmol) and 1-(2-aminoethyl)piperidine (64 μL, 0.45 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1→45:1) afforded compound (ZDR247) as a colourless solid (49 mg, 0.07 mmol, 46%). ¹H NMR (400 MHz, CDCl₃) δ 1.37 (4.5H, s), 1.52 (4.5H, s), 1.45 (2H, brs), 1.60 (4H, brs), 2.44 (4H, brs), 2.48 (2H, brs), 3.39 (2H, brq, J=5.4 Hz), 3.89-3.98 (2H, m), 4.71-4.77 (2H, m), 6.91-7.09 (1H, m), 7.39-7.52 (3H, m), 7.65 (2H, d, J=8.4 Hz), 7.83 (1H, brs), 8.04-8.09 (3H, m).

Example 149: 8-((4-(Trifluoromethyl)phenyl)sulfonamido)quinoline-2-carboxylic acid—Compound (ZDR251)

A solution of compound (ZDR019) (500 mg, 1.31 mmol) and potassium permanganate (350 mg, 2.22 mmol) in acetone (10 mL) was stirred at room temperature for 4 h. The mixture was then diluted with dichloromethane (30 mL) and washed with aqueous sodium hydrogen sulfate (30 mL, 1 M). The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 100:1→420:1) afforded compound (ZDR251) as an off-white solid (280 mg, 0.70 mmol, 53%). ¹H NMR (300 MHz, d₆-DMSO) δ 7.61 (1H, t, J=7.9 Hz), 7.68 (1H, dd, J=7.9 and 1.5 Hz), 7.74 (2H, d, J=8.5 Hz), 7.92 (1H, dd, J=7.9 and 1.5 Hz), 8.09 (2H, d, J=8.5 Hz), 8.19 (1H, d, J=8.5 Hz), 8.44 (1H, d, J=8.5 Hz).

Example 150: tert-Butyl (2-(methylamino)-2-oxoethyl)((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)carbamate—Compound (ZDR253)

A similar procedure to that described for the preparation of compound (ZDR234) was followed using compound (ZDR246) (100 mg, 0.15 mmol) and methylamine (0.5 mL, 1.0 mmol, 2 M in tetrahydrofuran) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1) afforded compound (ZDR253) as a colourless solid (58 mg, 0.10 mmol, 66%). ¹H NMR (400 MHz, CDCl₃) δ 1.37 (4.5H, s), 1.52 (4.5H, s), 2.81-2.82 (3H, m), 3.91-3.95 (2H, m), 4.72-4.78 (2H, m), 6.24-6.37 (1H, m), 7.39-7.50 (3H, m), 7.66 (2H, d, J=8.5 Hz), 7.83 (1H, brs), 8.02-8.06 (2H, m), 8.10 (1H, d, J=8.5 Hz), 9.16 (1H, brs).

Example 151: tert-Butyl 4-(N-(2-((dimethylamino)methyl)quinolin-8-yl)sulfamoyl)piperidine-1-carboxylate—Compound (ZDR256)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-chlorosulfonyl-piperidine-1-carboxylic acid tert-butyl ester (139 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) In dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1) afforded compound (ZDR256) as a yellow oil (60 mg, 0.13 mmol, 29%). ¹H NMR (400 MHz, CDCl₃) δ 1.40 (9H, s), 1.81 (2H, qd, J=12.5 and 4.5 Hz), 2.07-2.11 (2H, m), 2.31 (6H, s), 2.56 (2H, brs), 3.14 (1H, tt, J=11.9 and 3.7 Hz), 3.74 (2H, s), 4.14 (2H, brs), 7.47 (1H, d, J=7.6 Hz), 7.53 (1H, dd, J=8.2 and 1.2 Hz), 7.66 (1H, d, J=8.5 Hz), 8.36 (1H, dd, J=7.6 and 1.2 Hz), 8.15 (1H, d, J=8.5 Hz), 8.93 (1H, brs).

Example 152: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-(methylthio)benzenesulfonamide—Compound ZDR257

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 4-(thiomethyl)benzenesulfonyl chloride (109 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1→20:1) afforded compound (ZDR257) as a yellow solid (142 mg, 0.36 mmol, 81%). ¹H NMR (400 MHz, CDCl₃) δ 2.29 (6H, s), 2.40 (3H, s), 3.70 (2H, s), 7.09-7.12 (2H, m), 7.38-7.46 (2H, m), 7.58 (1H, d, J=8.5 Hz), 7.75-7.80 (3H, m), 8.06 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₉H₂₁N₃O₂S₂: 387.1; found [M+H]⁺: 388.1.

Example 153: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-6-methoxypyridine-3-sulfonamide—Compound (ZDR258)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), 6-methoxypyridine-3-sulfonyl chloride (101 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1→20:1) afforded compound (ZDR258) as a yellow solid (28 mg, 0.08 mmol, 18%). ¹H NMR (400 MHz, CDCl₃) δ 2.29 (6H, s), 3.70 (2H, s), 3.87 (3H, s), 6.60 (1H, d, J=8.8 Hz), 7.40-7.49 (2H, m), 7.59 (1H, d, J=8.5 Hz), 7.82 (1H, dd, J=7.5 and 1.6 Hz), 7.93-7.96 (1H, m), 8.07 (1H, d, J=8.5 Hz), 8.67 (1H, d, J=2.5 Hz); ESI-MS: m/z calcd for C₁₈H₂₀N₄O₃S: 372.1; found [M+H]⁺: 373.1.

Example 154: N-(2-((Dimethylamino)methyl)quinolin-8-yl)prop-2-ene-1-sulfonamide—Compound (ZDR259)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (90 mg, 0.44 mmol), propene-1-sulfonyl chloride (68 mg, 0.49 mmol) and triethylamine (68 μL, 0.49 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 100:1→20:1) afforded compound (ZDR259) as a yellow oil (55 mg, 0.18 mmol, 40%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.73 (2H, s), 3.84 (2H, d, J=7.3 Hz), 5.03-5.07 (1H, m), 5.25-5.27 (1H, m), 5.81-5.91 (1H, m), 7.45-7.54 (2H, m), 7.67 (1H, d, J=8.5 Hz), 7.87 (1H, dd, J=7.5 and 1.6 Hz), 8.14 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₅H₁₉N₃O₂S: 305.1; found [M+H]⁺: 306.1.

Example 155: N-(3-(Dimethylamino)propyl)-2-(((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)amino)acetamide di-trifluoroacetate—Compound (ZDR261)

A solution of compound (ZDR246) (100 mg, 0.15 mmol) and 3-(dimethylamino)-1-propylamine (56 μL, 0.45 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 h. Trifluoroacetic acid (5 mL) was added and the solution was stirred at room temperature for a further 3 h, and the solvent then removed in vacuo. Purification by RP-HLPC (30% to 90% A/B gradient over 60 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR261) as a white solid (40 mg, 0.05 mmol, 33%). ¹H NMR (400 MHz, d₆-acetone) δ 2.11 (2H, quin, J=7.0 Hz), 2.96 (6H, s), 3.38 (2H, t, J=7.0 Hz), 3.52 (2H, t, J=7.0 Hz), 4.24 (2H, s), 4.85 (2H, s), 7.52 (1H, t, J=8.0 Hz), 7.56 (1H, d, J=8.4 Hz), 7.63 (1H, dd, J=8.4 and 1.2 Hz), 7.81 (2H, d, J=8.3 Hz), 7.91 (1H, dd, J=7.8 and 1.2 Hz), 8.23 (2H, d, J=8.3 Hz), 8.29 (1H, d, J=8.4 Hz), 8.81 (1H, brs), 10.06 (1H, brs), 11.21 (1H, brs); ESI-MS: m/z calcd for C₂₄H₂₉F₃N₅O₃S: 523.2; found [M+Na]⁺: 546.1.

Example 156: N-(3-(Piperidin-1-yl)propyl)-2-(((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)amino)acetamide di-trifluoroacetate—Compound (ZDR262)

A similar procedure to that described for the preparation of compound (ZDR261) was followed using compound (ZDR246) (100 mg, 0.15 mmol) and N-(3-aminopropyl)piperidine (71 μL, 0.45 mmol) in dichloromethane (5 mL), with the subsequent addition of trifluoroacetic acid (5 mL). Purification by RP-HLPC (30% to 90% A/B gradient over 60 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR262) as a white solid (45 mg, 0.06 mmol, 40%). ¹H NMR (400 MHz, d₆-acetone) δ 1.45-1.52 (1H, m), 1.78-1.81 (1H, m), 1.85-1.91 (4H, m), 2.12 (2H, quin, J=7.2 Hz), 2.92-2.99 (2H, m), 3.31 (2H, t, J=7.2 Hz), 3.47-3.51 (2H, m), 3.58-3.62 (2H, m), 4.19 (2H, s), 4.84 (2H, s), 7.56 (1H, t, J=8.1 Hz), 7.61 (1H, d, J=8.5 Hz), 7.68 (1H, dd, J=8.1 and 1.2 Hz), 7.82 (2H, d, J=8.3 Hz), 7.95 (1H, dd, J=7.6 and 1.2 Hz), 8.24 (2H, d, J=8.3 Hz), 8.36 (1H, d, J=8.5 Hz), 8.67 (1H, brs), 10.04 (1H, brs), 10.83 (1H, brs); ESI-MS: m/z calcd for C₂₇H₃₂F₃N₅O₃S: 563.2; found [M+H]⁺: N/A.

Example 157: N-(2-((Dimethylamino)methyl)quinolin-8-yl)piperidine-4-sulfonamide di-trifluoroacetate—Compound (ZDR263)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR256) (50 mg, 0.11 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR263) as a pale yellow oil (60 mg, 0.11 mmol, quant.), which was used without further purification. ¹H NMR (400 MHz, d₆-acetone) δ 2.22-2.29 (2H, m), 2.39-2.43 (2H, m), 2.78-2.90 (1H, m), 3.23 (2H, s), 3.25 (6H, s), 3.69-3.75 (2H, m), 5.00 (2H, s), 7.53 (1H, t, J=8.0 Hz), 7.69-7.71 (2H, m), 7.85 (1H, d, J=7.5 Hz), 8.48 (1H, d, J=8.4 Hz), 8.67 (1H, brs), 9.42 (1H, s); ESI-MS: m/z calcd for C₁₇H₂₄N₄O₂S: 348.2; found [M+H]⁺: N/A.

Example 158: tert-Butyl (2-amino-2-oxoethyl)((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)carbamate—Compound (ZDR264)

A similar procedure to that described for the preparation of compound (ZDR234) was followed using compound (ZDR246) (100 mg, 0.15 mmol) and saturated methanolic ammonia (3 mL) in dichloromethane (3 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1→10:1) afforded compound (ZDR264) as a pale yellow solid (21 mg, 0.04 mmol, 26%). ¹H NMR (400 MHz, CDCl₃) δ 1.25 (4.5H, s), 1.52 (4.5H, s), 3.93-4.04 (2H, m), 4.74-4.78 (2H, m), 6.21-6.27 (1H, m), 6.92 (2H, brs), 7.31-7.33 (1H, m), 7.41 (1H, t, J=7.9 Hz), 7.46 (1H, d, J=7.5 Hz), 7.65 (2H, d, J=8.4 Hz), 7.80 (1H, d, J=7.5 Hz), 8.08 (2H, d, J=8.4 Hz), 8.17-8.19 (1H, m), 9.45 (1H, brs).

Example 159: N-(1,3-Dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)amino)acetamide trifluoroacetate—Compound (ZDR265)

A similar procedure to that described for the preparation of compound (ZDR234) was followed using compound (ZDR246) (100 mg, 0.15 mmol) and tris(hydroxymethyl)aminomethane (54 mg, 0.45 mmol) in dichloromethane/dimethylformamide (5 mL, 9:1 v/v). The resulting residue was then taken up in trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) and the mixture stirred at room temperature for 3 h, and the solvent removed in vacuo. Purification by RP-HLPC (30% to 90% A/B gradient over 60 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR265) as a white solid (15 mg, 0.02 mmol, 13%, over 2 steps). ¹H NMR (400 MHz, d₆-acetone) δ 3.82 (6H, s), 4.23 (2H, s), 4.84 (2H, s), 7.59 (1H, t, J=8.0 Hz), 7.64 (1H, d, J=8.5 Hz), 7.72 (1H, dd, J=8.4 and 1.4 Hz), 7.82 (2H, d, J=8.2 Hz), 7.98 (1H, dd, J=7.7 and 1.3 Hz), 8.22 (2H, d, J=8.2 Hz), 8.41 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₂₃H₂₅F₃N₄O₆S: 542.1; found [M+H]⁺: 543.2.

Example 160: 2-(((8-((4-(Trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)amino)acetamide trifluoroacetate—Compound (ZDR266)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR264) (20 mg, 0.03 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR266) as a yellow oil (16 mg, 0.03 mmol, quant.), which was used without further purification. ¹H NMR (400 MHz, d₆-acetone) δ 4.29 (2H, s), 4.93 (2H, s), 7.31 (1H, brs), 7.56 (1H, t, J=8.0 Hz), 7.64 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=8.2 Hz), 7.81 (2H, d, J=8.2 Hz), 7.97-7.99 (1H, m), 8.22 (2H, d, J=8.2 Hz), 8.40 (1H, d, J=8.4 Hz), 9.83 (1H, s); ESI-MS: m/z calcd for C₁₉H₁₇F₃N₄O₃S: 438.1; found [M+H]⁺: N/A.

Example 161: N-hydroxy-2-(((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)amino)acetamide trifluoroacetate—Compound (ZDR267)

A similar procedure to that described for the preparation of compound (ZDR234) was followed using compound (ZDR246) (100 mg, 0.15 mmol), hydroxylamine hydrochloride (31 mg, 0.45 mmol) and potassium carbonate (70 mg, 0.45 mmol) in aqueous tetrahydrofuran (5 mL, 1:1 v/v). The resulting residue was then taken up in trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) and the mixture stirred at room temperature for 3 h, and the solvent removed in vacuo. Purification by RP-HLPC (30% to 90% A/B gradient over 60 min, where A=water+0.1% trifluoroacetic acid and B=acetonitrile+0.1% trifluoroacetic acid) afforded compound (ZDR267) as a white solid (20 mg, 0.03 mmol, 20%). ¹H NMR (300 MHz, d₆-acetone) δ 4.32 (2H, s), 4.92 (2H, s), 7.56 (1H, t, J=8.0 Hz), 7.62 (1H, d, J=8.5 Hz), 7.68 (1H, dd, J=8.4 and 1.1 Hz), 7.74-7.76 (2H, m), 7.95 (1H, dd, J=7.6 and 1.3 Hz), 8.17-8.20 (2H, m), 8.36 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₉H₁₇F₃N₄O₄S: 454.4; found [M+H]⁺: N/A.

Example 162: N-(2-(Dimethylamino)ethyl)-2-(((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)amino)acetamide di-trifluoroacetate—Compound ZDR(268)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR234) (28 mg, 0.04 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR268) as a pale yellow solid (28 mg, 0.04 mmol, quant.), which was used without further purification. ¹H NMR (400 MHz, d₆-acetone) δ 3.15 (6H, s), 3.60-3.62 (2H, m), 3.94-3.97 (2H, m), 4.28 (2H, s), 4.93 (2H, s), 7.59 (1H, t, J=8.0 Hz), 7.64 (1H, d, J=8.5 Hz), 7.72 (1H, d, J=8.3 Hz), 7.82 (2H, d, J=8.2 Hz), 7.97-7.99 (1H, m), 8.22 (2H, d, J=8.2 Hz), 8.42 (1H, d, J=8.5 Hz), 8.62 (1H, t, J=5.6 Hz), 9.65 (1H, brs); ESI-MS: m/z calcd for C₂₃H₂₆F₃N₅O₃S: 509.2; found [M+H]⁺: N/A.

Example 163: N-(2-(Piperidin-1-yl)ethyl)-2-(((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)amino)acetamide di-trifluoroacetate—Compound—(ZDR269)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR247) (49 mg, 0.07 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR269) as a pale yellow oil (52 mg, 0.07 mmol, quant.), which was used without further purification. ¹H NMR (400 MHz, d₆-acetone) δ 1.50-1.59 (1H, m), 1.77-1.81 (1H, m), 1.90-1.96 (4H, m), 3.07-3.12 (2H, m), 3.52-3.54 (2H, m), 3.93-3.95 (4H, m), 4.28 (2H, s), 4.92 (2H, s), 7.57 (1H, t, J=8.0 Hz), 7.63 (1H, d, J=8.5 Hz), 7.71 (1H, d, J=8.2 Hz), 7.82 (2H, d, J=8.2 Hz), 7.99 (1H, d, J=7.7 Hz), 8.22 (2H, d, J=8.2 Hz), 8.41 (1H, d, J=8.5 Hz), 8.67 (1H, brt, J=5.6 Hz), 8.89 (1H, brs), 9.99 (1H, s); ESI-MS: m/z calcd for C₂₆H₃₀F₃N₅O₃S: 549.2; found [M+H]⁺: N/A.

Example 164: N-Methyl-2-(((8-((4-(trifluoromethyl)phenyl)sulfonamido)quinolin-2-yl)methyl)amino)acetamide trifluoroacetate—Compound (ZDR270)

A similar procedure to that described for the preparation of compound (ZDR124) was followed using compound (ZDR253) (58 mg, 0.10 mmol) and trifluoroacetic acid-dichloromethane (3 mL, 50% v/v) to afford compound (ZDR270) as a beige solid (55 mg, 0.10 mmol, quant.), which was used without further purification. ¹H NMR (400 MHz, d₆-acetone) δ 2.87 (3H, s), 4.26-4.36 (2H, m), 4.92-4.96 (2H, m), 7.56 (1H, t, J=8.0 Hz), 7.41 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=8.0 Hz), 7.80 (2H, d, J=8.2 Hz), 7.95 (1H, d, J=7.4 Hz), 8.21 (2H, d, J=8.2 Hz), 8.37 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₁₉F₃N₄O₃S: 452.1; found [M+H]⁺: N/A.

Example 165: 4-Bromo-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR305)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (95 mg, 0.47 mmol), 4-bromobenzenesulfonyl chloride (133 mg, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR305) as a pale yellow solid (160 mg, 0.38 mmol, 80%). ¹H NMR (400 MHz, CDCl₃) δ 2.27 (6H, s), 3.68 (2H, s), 7.37-7.46 (4H, m), 7.58 (1H, d, J=8.4 Hz), 7.71 (2H, d, J=8.5 Hz), 7.79 (1H, d, J=7.4 Hz), 8.04 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₈BrN₃O₂S: 419.0; found [M+H]⁺: 420.0.

Example 166: 4-(Difluoromethoxy)-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR306)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (95 mg, 0.47 mmol), 4-(difluoromethoxy)benzenesulfonyl chloride (126 mg, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR306) as a yellow solid (178 mg, 0.44 mmol, 92%). ¹H NMR (400 MHz, CDCl₃) δ 2.27 (6H, s), 3.69 (2H, s), 6.46 (1H, t, J=72.7 Hz), 7.00 (2H, d, J=8.8 Hz), 7.37-7.46 (2H, m), 7.56 (1H, d, J=8.5 Hz), 7.79 (1H, dd, J=7.4 and 1.4 Hz), 7.85-7.89 (2H, m), 8.04 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₉H₁₉F₂N₃O₃S: 407.1; found [M+H]⁺: 408.1.

Example 167: 4-(tert-Butyl)-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR307)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (95 mg, 0.47 mmol), 4-tert-butylbenzenesulfonyl chloride (121 mg, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR307) as a white solid (173 mg, 0.44 mmol, 92%). ¹H NMR (400 MHz, CDCl₃) δ 1.20 (9H, s), 2.28 (6H, s), 3.70 (2H, s), 7.31-7.34 (2H, m), 7.36-7.42 (2H, m), 7.57 (1H, d, J=8.5 Hz), 7.79-7.82 (3H, m), 8.03 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₂₂H₂₇N₃O₂S: 397.2; found [M+H]⁺: 398.2.

Example 168: Methyl 3-(N-(2-((dimethylamino)methyl)quinolin-8-yl)sulfamoyl)benzoate—Compound (ZDR308)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (95 mg, 0.47 mmol), 3-chlorosulfonyl-benzoic acid methyl ester (122 mg, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR308) as an orange oil (122 mg, 0.31 mmol, 64%). ¹H NMR (400 MHz, CDCl₃) δ 2.25 (6H, s), 3.67 (2H, s), 3.84 (3H, s), 7.34-7.42 (3H, m), 7.53 (1H, d, J=8.4 Hz), 7.79 (1H, d, J=7.0 Hz), 7.99-8.01 (3H, m), 8.53 (1H, s); ESI-MS: m/z calcd for C₂₀H₂₁N₃O₄S: 399.1; found [M+H]⁺: 400.1.

Example 169: 3-Bromo-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR309)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (95 mg, 0.47 mmol), 3-bromobenzenesulfonyl chloride (133 mg, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR309) as a yellow solid (160 mg, 0.38 mmol, 80%). ¹H NMR (400 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 7.14 (1H, t, J=7.9 Hz), 7.38-7.49 (3H, m), 7.56 (1H, d, J=8.4 Hz), 7.75 (1H, d, J=7.9 Hz), 7.80 (1H, dd, J=7.5 and 1.2 Hz), 8.03-8.05 (2H, m); ESI-MS: m/z calcd for C₁₈H₁₈BrN₃O₂S: 419.0; found [M+H]⁺: 420.0.

Example 170: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3-(methylsulfonyl)benzenesulfonamide—Compound (ZDR310)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (88 mg, 0.44 mmol), 3-methylsulfonylbenzenesulfonyl chloride (122 mg, 0.48 mmol) and triethylamine (67 μL, 0.48 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR310) as a pale yellow foam (137 mg, 0.33 mmol, 75%). ¹H NMR (400 MHz, CDCl₃) δ 2.30 (6H, s), 2.92 (3H, s), 3.72 (2H, s), 7.42-7.59 (4H, m), 7.85 (1H, dd, J=7.4 and 1.1 Hz), 7.96 (1H, d, J=7.9 Hz), 8.06 (1H, d, J=8.4 Hz), 8.13 (1H, d, J=8.4 Hz), 8.43 (1H, s); ESI-MS: m/z calcd for C₁₉H₂₁N₃O₄S₂: 419.1; found [M+H]⁺: 420.1.

Example 171: 3-Acetyl-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR311)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (130 mg, 0.65 mmol), 3-acetylbenzenesulfonyl chloride (155 mg, 0.71 mmol) and triethylamine (99 μL, 0.71 mmol) in dichloromethane (6 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR311) as a brown oil (201 mg, 0.52 mmol, 81%). ¹H NMR (400 MHz, CDCl₃) δ 2.27 (6H, s), 2.50 (3H, s), 3.69 (2H, s), 7.39-7.47 (3H, m), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, dd, J=7.5 and 1.5 Hz), 7.96-7.99 (1H, m), 8.03-8.07 (2H, m), 8.41 (1H, t, J=1.7 Hz); ESI-MS: m/z calcd for C₂₀H₂₁N₃O₃S: 383.1; found [M+H]⁺: 384.1.

Example 172: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3-fluorobenzenesulfonamide—Compound (ZDR312)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (88 mg, 0.44 mmol), 3-fluorobenzenesulfonyl chloride (94 mg, 0.48 mmol) and triethylamine (67 μL, 0.48 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR312) as brown solid (138 mg, 0.38 mmol, 88%). ¹H NMR (400 MHz, CDCl₃) δ 2.30 (6H, s), 3.72 (2H, s), 7.08-7.13 (1H, m), 7.27-7.33 (1H, m), 7.40-7.49 (2H, m), 7.58-7.62 (2H, m), 7.65-7.67 (1H, m), 7.82 (1H, dd, J=7.5 and 1.5 Hz), 8.07 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₈H₁₈FN₃O₂S: 359.1; found [M+H]⁺: 360.1.

Example 173: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3-nitrobenzenesulfonamide—Compound (ZDR313)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (88 mg, 0.44 mmol), 3-nitrobenzenesulfonyl chloride (107 mg, 0.48 mmol) and triethylamine (67 μL, 0.48 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR313) as a red/orange oil (67 mg, 0.17 mmol, 40%). ¹H NMR (400 MHz, CDCl₃) δ 2.29 (6H, s), 3.72 (2H, s), 7.41-7.59 (4H, m), 7.85 (1H, dd, J=7.5 and 1.2 Hz), 8.06 (1H, d, J=8.5 Hz), 8.18 (1H, m), 8.24 (1H, m), 8.74 (1H, t, J=1.9 Hz); ESI-MS: m/z calcd for C₁₈H₁₈N₄O₄S: 386.1; found [M+H]⁺: 387.1.

Example 174: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3-methoxybenzenesulfonamide—Compound (ZDR314)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (88 mg, 0.44 mmol), 3-methoxybenzene sulfonyl chloride (99 mg, 0.48 mmol) and triethylamine (67 μL, 0.48 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR314) as a pale brown solid (139 mg, 0.37 mmol, 86%). ¹H NMR (400 MHz, CDCl₃) δ 2.29 (6H, s), 3.70 (2H, s), 3.70 (3H, s), 6.91-6.94 (1H, m), 7.22 (1H, t, J=8.0 Hz), 7.37-7.47 (4H, m), 7.59 (1H, d, J=8.5 Hz), 7.82 (1H, dd, J=7.5 and 1.5 Hz), 8.06 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₉H₂₁N₃O₃S: 371.1; found [M+H]⁺: 372.1.

Example 175: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3-methylbenzenesulfonamide—Compound (ZDR315)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (88 mg, 0.44 mmol), 3-toluenesulfonyl chloride (92 mg, 0.48 mmol) and triethylamine (67 μL, 0.48 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR315) as a pale yellow solid (124 mg, 0.35 mmol, 80%). ¹H NMR (400 MHz, CDCl₃) δ 2.28 (3H, s), 2.35 (6H, s), 3.79 (2H, s), 7.19-7.22 (2H, m), 7.39-7.46 (2H, m), 7.59 (1H, d, J=8.5 Hz), 7.67-7.72 (2H, m), 7.79 (1H, dd, J=7.0 and 1.5 Hz), 8.07 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₉H₂₁N₃O₂S: 355.1; found [M+H]⁺: 356.1.

Example 176: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3,3,3-trifluoropropane-1-sulfonamide—Compound (ZDR316)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), 3,3,3-trifluoropropane-1-sulfonyl chloride (69 μL, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR316) as an orange solid (144 mg, 0.40 mmol, 80%). ¹H NMR (400 MHz, CDCl₃) δ 2.34 (6H, s), 2.65-2.77 (2H, m), 3.27-3.31 (2H, m), 3.78 (2H, s), 7.51 (1H, t, J=7.9 Hz), 7.59-7.61 (1H, m), 7.68 (1H, d, J=8.4 Hz), 7.85 (1H, dd, J=7.5 and 1.0 Hz), 8.18 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₈F₃N₃O₂S: 361.1; found [M+H]⁺: 362.1.

Example 177: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-1-phenylmethanesulfonamide—Compound (ZDR317)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), phenylmethanesulfonyl chloride (104 mg, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR317) as a brown oil (44 mg, 0.12 mmol, 25%). ¹H NMR (400 MHz, CDCl₃) δ 2.29 (6H, s), 3.63 (2H, s), 4.41 (2H, s), 7.07-7.09 (2H, m), 7.12-7.16 (2H, m), 7.23-7.26 (1H, m), 7.46 (1H, t, J=7.8 Hz), 7.52 (1H, dd, J=8.0 and 1.5 Hz), 7.66 (1H, d, J=8.4 Hz), 7.81 (1H, dd, J=7.5 and 1.5 Hz), 8.14 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₂₁N₃O₂S: 355.1; found [M+H]⁺: 356.1.

Example 178: N-(2-((Dimethylamino)methyl)quinolin-8-yl)propane-2-sulfonamide—Compound (ZDR318)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (170 mg, 0.84 mmol), 2-propanesulfonyl chloride (104 μL, 0.93 mmol) and triethylamine (130 μL, 0.93 mmol) in dichloromethane (8 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR318) as a dark brown solid (206 mg, 0.67 mmol, 79%). ¹H NMR (400 MHz, CDCl₃) δ 1.26-1.28 (6H, m), 2.74 (6H, s), 3.34-3.35 (1H, m), 4.24 (2H, s), 6.98-7.01 (1H, m), 7.14-7.18 (1H, m), 7.33-7.43 (2H, m), 8.11-8.15 (1H, m); ESI-MS: m/z calcd for C₁₅H₂₁N₃O₂S: 307.1; found [M+H]⁺: N/A.

Example 179: Methyl 3-(N-(2-((dimethylamino)methyl)quinolin-8-yl)sulfamoyl)thiophene-2-carboxylate—Compound (ZDR319)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), methyl 3-chlorosulfonylthiophene-2-carboxylate (132 mg, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR319) as an orange solid (78 mg, 0.19 mmol, 39%). ¹H NMR (400 MHz, CDCl₃) δ 2.30 (6H, s), 3.73 (2H, s), 3.97 (3H, s), 7.35-7.45 (3H, m), 7.57-7.62 (2H, m), 7.87 (1H, dd, J=7.8 and 1.5 Hz), 8.05 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₈H₁₉N₃O₄S₂: 405.1; found [M+H]⁺: 406.1.

Example 180: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-1-(4-(trifluoromethyl)phenyl)methanesulfonamide—Compound (ZDR320)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), 4-(trifluoromethyl)benzylsulfonyl chloride (141 mg, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR320) as a pale brown oil (163 mg, 0.38 mmol, 77%). ¹H NMR (400 MHz, CDCl₃) δ 2.28 (6H, s), 3.61 (2H, s), 4.45 (2H, s), 7.19 (2H, d, J=8.1 Hz), 7.37 (2H, d, J=8.1 Hz), 7.42-7.54 (2H, m), 7.65 (1H, d, J=8.4 Hz), 7.82 (1H, dd, J=7.6 and 1.6 Hz), 8.14 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₂₀H₂₀F₃N₃O₂S: 423.1; found [M+H]⁺: 424.1.

Example 181: N-(2-((Dimethylamino)methyl)quinolin-8-yl)butane-1-sulfonamide—Compound (ZDR321)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), 1-butane sulfonyl chloride (71 μL, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR321) as an orange oil (100 mg, 0.31 mmol, 63%). ¹H NMR (400 MHz, CDCl₃) δ 0.78 (3H, t, J=7.4 Hz), 1.26-1.35 (2H, m), 1.74-1.82 (2H, m), 2.31 (6H, s), 3.08-3.12 (2H, m), 3.73 (2H, s), 7.43-7.52 (2H, m), 7.66 (1H, d, J=8.4 Hz), 7.82 (1H, dd, J=7.5 and 1.5 Hz), 8.13 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₆H₂₃N₃O₂S: 321.2; found [M+H]⁺: 322.2.

Example 182: 6-Chloro-N-(2-((dimethylamino)methyl)quinolin-8-yl)pyridine-3-sulfonamide—Compound (ZDR322)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), 2-chloropyridine-5-sulfonyl chloride (116 mg, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR322) as a yellow solid (90 mg, 0.24 mmol, 48%). ¹H NMR (400 MHz, CDCl₃) δ 2.28 (6H, s), 3.69 (2H, s), 7.26-7.28 (1H, m), 7.44 (1H, t, J=7.9 Hz), 7.52 (1H, dd, J=7.9 and 1.5 Hz), 7.58 (1H, d, J=8.5 Hz), 7.85 (1H, dd, J=7.5 and 0.9 Hz), 8.04-8.09 (2H, m), 8.82-8.83 (1H, m); ESI-MS: m/z calcd for C₁₇H₁₇ClN₄O₂S: 376.1; found [M+H]⁺: 377.1.

Example 183: N-(2-((Dimethylamino)methyl)quinolin-8-yl)cyclopropanesulfonamide—Compound (ZDR323)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), cyclopropanesulfonyl chloride (56 μL, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR323) as a brown solid (41 mg, 0.13 mmol, 27%). ¹H NMR (400 MHz, CDCl₃) δ 0.83-0.89 (2H, m), 1.25-1.29 (2H, m), 2.33 (6H, s), 2.49-2.56 (1H, m), 3.75 (2H, s), 7.45-7.54 (2H, m), 7.66 (1H, d, J=8.5 Hz), 7.88 (1H, dd, J=7.5 and 1.5 Hz), 8.14 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₅H₁₉N₃O₂S: 305.1; found [M+H]⁺: 306.1.

Example 184: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-formylbenzenesulfonamide—Compound (ZDR324)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (95 mg, 0.47 mmol), 4-formylbenzene-1-sulfonyl chloride (106 mg, 0.52 mmol) and triethylamine (72 μL, 0.52 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR324) as a yellow oil (70 mg, 0.19 mmol, 40%). ¹H NMR (400 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 7.39-7.48 (2H, m), 7.56 (1H, d, J=8.4 Hz), 7.80-7.85 (3H, m), 8.03-8.06 (3H, m), 9.94 (1H, s); ESI-MS: m/z calcd for C₁₉H₁₉N₃O₃S: 369.1; found [M+H]⁺: N/A.

Example 185: 5-Chloro-N-(2-((dimethylamino)methyl)quinolin-8-yl)thiophene-2-sulfonamide—Compound (ZDR326)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (95 mg, 0.47 mmol), 5-chlorothiophene-2-sulfonyl chloride (69 μL, 0.52 mmol) and triethylamine (72 μL, 0.52 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR326) as a yellow solid (38 mg, 0.10 mmol, 21%). ¹H NMR (400 MHz, CDCl₃) δ 2.29 (6H, s), 3.71 (2H, s), 6.70 (1H, d, J=4.0 Hz), 7.34 (1H, d, J=4.0 Hz), 7.45-7.54 (2H, m), 7.62 (1H, d, J=8.4 Hz), 7.86 (1H, dd, J=7.5 and 1.3 Hz), 8.10 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₆H₁₆ClN₃O₂S₂: 381.0; found [M+H]⁺: N/A.

Example 186: N-(3-(N-(2-((Dimethylamino)methyl)quinolin-8-yl)sulfamoyl)phenyl)acetamide—Compound (ZDR327)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (95 mg, 0.47 mmol), 3-acetamidobenzene-1-sulfonyl chloride (121 mg, 0.52 mmol) and triethylamine (72 μL, 0.52 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR327) as a yellow solid (31 mg, 0.08 mmol, 16%). ¹H NMR (400 MHz, CDCl₃) δ 2.12 (3H, s), 2.28 (6H, s), 3.71 (2H, s), 7.22-7.30 (1H, m), 7.37-7.41 (1H, m), 7.43-7.46 (1H, m), 7.50 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=7.9 Hz), 7.83 (1H, dd, J=7.5 Hz and 1.5 Hz), 7.96 (1H, s), 7.99-8.01 (1H, m), 8.04 (1H, d, J=8.4 Hz), 8.10 (1H, br s); ESI-MS: m/z calcd for C₂₀H₂₂N₄O₃S: 398.1; found [M+H]⁺: N/A.

Example 187: N-(2-((Dimethylamino)methyl)quinolin-8-yl)pyridine-3-sulfonamide—Compound (ZDR328)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (95 mg, 0.47 mmol), pyridine-3-sulfonyl chloride (63 μL, 0.52 mmol) and triethylamine (72 μL, 0.52 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR328) as a yellow solid (123 mg, 0.36 mmol, 76%). ¹H NMR (400 MHz, CDCl₃) δ 2.28 (6H, s), 3.70 (2H, s), 7.24-7.27 (1H, m), 7.41-7.45 (1H, m), 7.48-7.50 (1H, m), 7.59 (1H, d, J=8.4 Hz), 7.85 (1H, dd, J=7.5 and 1.2 Hz), 8.06 (1H, d, J=8.4 Hz), 8.12-8.15 (1H, m), 8.61 (1H, dd, J=5.0 and 1.5 Hz), 9.06-9.07 (1H, m); ESI-MS: m/z calcd for C₁₇H₁₈N₄O₂S: 342.1; found [M+H]⁺: 343.1.

Example 188: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-4-((trifluoromethyl)thio)benzenesulfonamide—Compound (ZDR330)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (84 mg, 0.42 mmol), 4-(trifluoromethylsulfanyl)benzenesulfonyl chloride (127 mg, 0.46 mmol) and triethylamine (64 μL, 0.46 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR330) as an orange solid (140 mg, 0.32 mmol, 76%). ¹H NMR (400 MHz, CDCl₃) δ 2.29 (6H, s), 3.69 (2H, s), 7.41-7.50 (2H, m), 7.58-7.60 (3H, m), 7.83 (1H, dd, J=7.5 and 1.7 Hz), 7.90 (2H, d, J=8.4 Hz), 8.06 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₉H₁₈F₃N₃O₂S₂: 441.1; found [M+H]⁺: 442.1.

Example 189: 3-(N-(2-((Dimethylamino)methyl)quinolin-8-yl)sulfamoyl)benzamide—Compound (ZDR331)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (84 mg, 0.42 mmol), 3-carbamoylbenzene-1-sulfonyl chloride (101 mg, 0.46 mmol) and triethylamine (64 μL, 0.46 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR331) as a yellow solid (123 mg, 0.32 mmol, 77%). ¹H NMR (400 MHz, CDCl₃) δ 2.26 (6H, s), 3.70 (2H, s), 6.26 (1H, br s), 6.98 (1H, br s), 7.33-7.48 (4H, m), 7.80 (1H, dd, J=7.5 and 1.6 Hz), 7.94 (2H, t, J=6.8 Hz), 8.01 (1H, d, J=8.4 Hz), 8.44 (1H, s); ESI-MS: m/z calcd for C₁₉H₂₀N₄O₃S: 384.1; found [M+H]⁺: 385.1.

Example 190: Methyl (4-(N-(2-((dimethylamino)methyl)quinolin-8-yl)sulfamoyl)phenyl)carbamate—Compound (ZDR332)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (84 mg, 0.42 mmol), methyl N-[4-(chlorosulfonyl)phenyl]carbamate (115 mg, 0.46 mmol) and triethylamine (64 μL, 0.46 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR332) as a brown oil (153 mg, 0.37 mmol, 88%). ¹H NMR (400 MHz, CDCl₃) δ 2.27 (6H, s), 3.67 (3H, s), 3.69 (2H, s), 7.32-7.42 (4H, m), 7.53 (1H, d, J=8.5 Hz), 7.74-7.77 (3H, m), 8.01 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₂₀H₂₁N₄O₄S: 414.1; found [M+H]⁺: 415.1.

Example 191: tert-Butyl (4-(N-(2-((dimethylamino)methyl)quinolin-8-yl)sulfamoyl)phenyl)carbamate—Compound (ZDR333)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (113 mg, 0.56 mmol), tert-butyl[4-(chlorosulfonyl)phenyl]carbamate (180 mg, 0.62 mmol) and triethylamine (86 μL, 0.62 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR333) as a white foam (209 mg, 0.46 mmol, 82%). ¹H NMR (400 MHz, CDCl₃) δ 1.46 (9H, s), 2.29 (6H, s), 3.71 (2H, s), 6.58 (1H, br s), 7.30-7.33 (2H, m), 7.36-7.44 (2H, m), 7.58 (1H, d, J=8.5 Hz), 7.76-7.81 (3H, m), 8.05 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₂₃H₂₈N₄O₄S: 456.2; found [M+H]⁺: 457.2.

Example 192: 2,4-Dichloro-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR335)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), 2,4-dichlorobenzenesulfonyl chloride (134 mg, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR335) as a pale yellow solid (156 mg, 0.38 mmol, 77%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.74 (2H, s), 7.27 (1H, dd, J=8.5 and 2.0 Hz), 7.32 (1H, d, J=2.0 Hz), 7.35 (1H, d, J=7.8 Hz), 7.42 (1H, dd, J=8.4 and 1.1 Hz), 7.64 (1H, d, J=8.5 Hz), 7.71 (1H, dd, J=7.6 and 1.3 Hz), 8.06 (1H, d, J=8.4 Hz), 8.10 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₈H₁₇Cl₂N₃O₂S: 409.0; found [M+H]⁺: 410.0.

Example 193: 2,3-Dichloro-N-(2-((dimethylamino)methyl)quinolin-8-yl)benzenesulfonamide—Compound (ZDR336)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), 2,3-dichlorobenzenesulfonyl chloride (134 mg, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR336) as a tan solid (169 mg, 0.41 mmol, 83%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.75 (2H, s), 7.24 (1H, t, J=7.9 Hz), 7.33 (1H, t, J=7.9 Hz), 7.41 (1H, d, J=7.9 Hz), 7.50 (1H, dd, J=7.9 and 1.1 Hz), 7.63 (1H, d, J=8.4 Hz), 7.73 (1H, d, J=7.6 Hz), 8.05 (1H, d, J=8.4 Hz), 8.10 (1H, dd, J=7.9 and 1.3 Hz); ESI-MS: m/z calcd for C₁₈H₁₇Cl₂N₃O₂S: 409.0; found [M+H]⁺: 410.1.

Example 194: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-2,4,5-trifluorobenzenesulfonamide—Compound (ZDR337)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), 2,4,5-trifluorobenzenesulfonyl chloride (76 μL, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR337) as a pale yellow solid (190 mg, 0.48 mmol, 97%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.75 (2H, s), 6.85-6.92 (1H, m), 7.40 (1H, t, J=8.0 Hz), 7.49 (1H, dd, J=8.4 and 1.2 Hz), 7.63 (1H, d, J=8.5 Hz), 7.76 (1H, dd, J=7.6 and 1.1 Hz), 7.81 (1H, td, J=8.8 and 6.4 Hz), 8.09 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₈H₁₆F₃N₃O₂S: 395.1; found [M+H]⁺: 396.1.

Example 195: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-3,4-difluorobenzenesulfonamide—Compound (ZDR338)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), 3,4-difluorobenzenesulfonyl chloride (73 μL, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR338) as a pale orange solid (180 mg, 0.48 mmol, 96%). ¹H NMR (400 MHz, CDCl₃) δ 2.30 (6H, s), 3.72 (2H, s), 7.06-7.12 (1H, m), 7.41-7.44 (1H, m), 7.49 (1H, dd, J=8.4 and 1.3 Hz), 7.57 (1H, d, J=8.5 Hz), 7.63-7.67 (1H, m), 7.73-7.78 (1H, m), 7.82 (1H, dd, J=7.5 and 1.3 Hz), 8.07 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₈H₁₇F₂N₃O₂S: 377.1; found [M+H]⁺: 378.1.

Example 196: N-(2-((Dimethylamino)methyl)quinolin-8-yl)isoquinoline-5-sulfonamide—Compound (ZDR339)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), isoquinoline-5-sulfonylchloride hydrochloride (144 mg, 0.55 mmol) and triethylamine (152 μL, 1.09 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR339) as a pale yellow solid (88 mg, 0.22 mmol, 44%). ¹H NMR (400 MHz, CDCl₃) δ 2.25 (6H, s), 3.62 (2H, s), 7.32-7.39 (2H, m), 7.50 (1H, d, J=8.4 Hz), 7.55 (1H, t, J=7.8 Hz), 7.74 (1H, dd, J=7.5 and 1.6 Hz), 7.97 (1H, d, J=8.4 Hz), 8.03-8.05 (1H, m), 8.47 (1H, dd, J=7.5 and 1.6 Hz), 8.61-8.67 (2H, m), 9.20 (1H, d, J=0.7 Hz); ESI-MS: m/z calcd for C₂₁H₂₀N₄O₂S: 392.1; found [M+H]⁺: 393.1.

Example 197: N-(2-((Dimethylamino)methyl)quinolin-8-yl)quinoline-8-sulfonamide—Compound (ZDR340)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (100 mg, 0.50 mmol), 8-quinolinesulfonyl chloride (124 mg, 0.55 mmol) and triethylamine (76 μL, 0.55 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR340) as a grey solid (70 mg, 0.17 mmol, 34%). ¹H NMR (400 MHz, d₆-DMSO) δ 2.30 (6H, s), 3.81 (2H, s), 7.41 (1H, t, J=8.0 Hz), 7.50 (1H, dd, J=8.8 and 1.5 Hz), 7.57 (1H, d, J=8.4 Hz), 7.64-7.72 (2H, m), 7.83 (1H, dd, J=7.5 and 1.7 Hz), 8.20-8.23 (2H, m), 8.42-8.46 (2H, m), 9.14 (1H, dd, J=4.0 and 1.5 Hz); ESI-MS: m/z calcd for C₂₁H₂₀N₄O₂S: 392.1; found [M+H]⁺: 393.1.

Example 198: N-(2-((Butylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR401)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), n-butylamine (80 μL, 0.81 mmol) and sodium triacetoxyborohydride (122 mg, 0.58 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR401) as a pale yellow solid (76 mg, 0.17 mmol, 66%). ¹H NMR (400 MHz, CDCl₃) δ 0.90 (3H, t, J=7.4 Hz), 1.31-1.40 (2H, m), 1.68-1.75 (2H, m), 2.89 (2H, t, J=7.6 Hz), 4.29 (2H, s), 7.36-7.45 (3H, m), 7.54 (2H, d, J=8.5 Hz), 7.79 (1H, dd, J=7.5 and 1.5 Hz), 8.02-8.08 (3H, m), 8.93 (2H, brs); ESI-MS: m/z calcd for C₂₁H₂₂F₃N₃O₂S: 437.1; found [M+H]⁺: 438.1.

Example 199: N-(2-((sec-Butylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR402)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), sec-butylamine (80 μL, 0.79 mmol) and sodium triacetoxyborohydride (120 mg, 0.57 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR402) as a pale yellow solid (32 mg, 0.07 mmol, 28%). ¹H NMR (400 MHz, CDCl₃) δ 0.95 (3H, t, J=7.6 Hz), 1.17 (3H, d, J=6.4 Hz), 1.42-1.53 (1H, m), 1.59-1.71 (1H, m), 2.73-2.81 (1H, m), 4.08-4.18 (2H, m), 5.00 (2H, brs), 7.39-7.43 (1H, m), 7.45-7.48 (2H, m), 7.60 (2H, d, J=8.2 Hz), 7.81 (1H, dd, J=7.5 and 1.5 Hz), 8.03-8.07 (3H, m); ESI-MS: m/z calcd for C₂₁H₂₂F₃N₃O₂S: 437.1; found [M+H]⁺: 438.2.

Example 200: N-(2-((Iso-Butylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR403)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), iso-butylamine (80 μL, 0.81 mmol) and sodium triacetoxyborohydride (111 mg, 0.52 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR403) as a yellow oil (73 mg, 0.17 mmol, 63%). ¹H NMR (400 MHz, CDCl₃) δ 0.98 (6H, d, J=6.6 Hz), 1.92 (1H, m), 2.57 (2H, d, J=6.8 Hz), 4.15 (2H, s), 6.21 (2H, brs), 7.40-7.49 (3H, m), 7.59 (2H, d, J=8.4 Hz), 7.82 (1H, dd, J=7.4 and 1.5 Hz), 8.03-8.08 (3H, m); ESI-MS: m/z calcd for C₂₁H₂₂F₃N₃O₂S: 437.1; found [M+H]⁺: 438.1.

Example 201: N-(2-((Cyclopentylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR404)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), cyclopentylamine (80 μL, 0.81 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR404) as a yellow solid (79 mg, 0.18 mmol, 67%). ¹H NMR (400 MHz, CDCl₃) δ 1.03-1.68 (8H, m), 2.71-2.77 (1H, m), 4.21 (2H, s), 7.27-7.36 (3H, m), 7.50 (2H, d, J=8.3 Hz), 7.72 (1H, dd, J=6.7 and 1.9 Hz), 7.93 (1H, d, J=8.3 Hz), 8.03 (2H, d, J=8.3 Hz), 8.50 (2H, brs); ESI-MS: m/z calcd for C₂₂H₂₂F₃N₃O₂S: 449.1; found [M+H]⁺: N/A.

Example 202: N-(2-((Cyclohexylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR405)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), cyclohexylamine (90 μL, 0.79 mmol) and sodium triacetoxyborohydride (112 mg, 0.53 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR405) as a pale yellow solid (15 mg, 0.03 mmol, 12%). ¹H NMR (400 MHz, CDCl₃) δ 0.83-0.90 (2H, m), 1.48-1.61 (4H, m), 1.70-1.81 (2H, m), 1.87-1.93 (2H, m), 3.20-3.22 (1H, m), 4.11 (2H, s), 7.39-7.48 (3H, m), 7.60 (2H, d, J=8.4 Hz), 7.81 (1H, dd, J=7.5 and 1.5 Hz), 8.02-8.07 (3H, m); ESI-MS: m/z calcd for C₂₃H₂₄F₃N₃O₂S: 463.2; found [M+H]⁺: N/A.

Example 203: N-(2-(((Cyclohexylmethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR406)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), cyclohexanemethylamine (110 μL, 0.85 mmol) and sodium triacetoxyborohydride (118 mg, 0.56 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR406) as a pale yellow solid (56 mg, 0.12 mmol, 45%). ¹H NMR (400 MHz, CDCl₃) δ 0.92-1.87 (11H, m), 2.69 (2H, d, J=6.9 Hz), 4.28 (2H, s), 7.38-7.47 (3H, m), 7.58 (2H, d, J=8.5 Hz), 7.81 (1H, dd, J=7.4 and 1.5 Hz), 8.05-8.10 (3H, m), 8.34 (2H, brs); ESI-MS: m/z calcd for C₂₄H₂₆F₃N₃O₂S: 477.2; found [M+H]⁺: 478.2.

Example 204: N-(2-(Pyrrolidin-1-ylmethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR407)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), pyrrolidine (70 μL, 0.84 mmol) and sodium triacetoxyborohydride (115 mg, 0.54 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR407) as a tan solid (37 mg, 0.09 mmol, 33%). ¹H NMR (400 MHz, CDCl₃) δ 1.85-1.89 (4H, m), 2.64-2.69 (4H, m), 3.99 (2H, s), 7.41-7.45 (1H, m), 7.47-7.50 (1H, m), 7.54 (1H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.87 (1H, dd, J=7.5 and 1.5 Hz), 8.02 (2H, d, J=8.5 Hz), 8.07 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₂₁H₂₀F₃N₃O₂S: 435.1; found [M+H]⁺: 436.1.

Example 205: N-(2-(Azepan-1-ylmethyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR408)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), hexamethyleneimine (90 μL, 0.80 mmol) and sodium triacetoxyborohydride (117 mg, 0.55 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR408) as a brown solid (105 mg, 0.23 mmol, 86%). ¹H NMR (400 MHz, CDCl₃) δ 1.64-1.70 (8H, m), 2.71-2.76 (4H, m), 3.96 (2H, s), 7.41 (1H, t, J=7.9 Hz), 7.46-7.49 (1H, m), 7.59 (2H, d, J=8.4 Hz), 7.64 (1H, d, J=8.4 Hz), 7.84 (1H, dd, J=7.5 and 1.0 Hz), 8.01-8.06 (3H, m), 9.52 (1H, brs); ESI-MS: m/z calcd for C₂₃H₂₄F₃N₃O₂S: 463.2; found [M+H]⁺:464.2.

Example 206: N-(2-((Dipropylamino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide—Compound (ZDR409)

A similar procedure to that described for the preparation of compound (ZDR022) was followed using compound (ZDR019) (100 mg, 0.26 mmol), dipropylamine (110 μL, 0.80 mmol) and sodium triacetoxyborohydride (121 mg, 0.57 mmol) in dichloromethane (5 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→15:1) afforded compound (ZDR409) as a tan solid (23 mg, 0.05 mmol, 19%). ¹H NMR (400 MHz, CDCl₃) δ 0.86 (6H, t, J=7.2 Hz), 1.45-1.54 (4H, m), 2.44 (4H, t, J=7.2 Hz), 3.81 (2H, s), 7.39-7.43 (1H, m), 7.46-7.49 (1H, m), 7.60 (2H, d, J=8.5 Hz), 7.68 (1H, d, J=8.5 Hz), 7.82 (1H, dd, J=7.5 and 1.3 Hz), 8.00-8.05 (3H, m); ESI-MS: m/z calcd for C₂₃H₂₆F₃N₃O₂S: 465.2; found [M+H]⁺: 466.2.

Example 207: N-(2-((Dimethylamino)methyl)quinolin-8-yl)ethenesulfonamide—Compound (ZDR500)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (79 mg, 0.36 mmol), ethenesulfonyl chloride (50 mg, 0.36 mmol) and triethylamine (56 μL, 0.40 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR500) as a yellow oil (58 mg, 0.20 mmol, 55%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 3.74 (2H, s), 5.88 (1H, d, J=9.8 Hz), 6.36 (1H, d, J=16.6 Hz), 6.56 (1H, dd, J=16.6 and 9.8 Hz), 7.44 (1H, t, J=7.9 Hz), 7.50 (1H, dd, J=8.4 and 1.4 Hz), 7.65 (1H, d, J=8.4 Hz), 7.72 (1H, dd, J=7.5 and 1.4 Hz), 8.12 (1H, d, J=8.4 Hz); ESI-MS: m/z calcd for C₁₄H₁₇N₃O₂S: 291.1; found [M+H]⁺: 292.1.

Example 208: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-1-(5-methylisoxazol-3-yl)methanesulfonamide—Compound (ZDR501)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (56 mg, 0.25 mmol), (5-methyl-1,2-oxazol-3-yl)methanesulfonyl chloride (50 mg, 0.25 mmol) and triethylamine (39 μL, 0.28 mmol) in dichloromethane (3 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR501) as a pale yellow oil (47 mg, 0.13 mmol, 51%). ¹H NMR (400 MHz, CDCl₃) δ 2.32 (6H, s), 2.38 (3H, s), 3.70 (2H, s), 4.45 (2H, s), 6.20 (1H, s), 7.45-7.49 (1H, m), 7.55 (1H, d, J=8.0 Hz), 7.65 (1H, d, J=8.5 Hz), 7.86 (1H, d, J=7.5 Hz), 8.14 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₇H₂₀N₄O₃S: 360.1; found [M+H]⁺: 361.1.

Example 209: N-(2-((Dimethylamino)methyl)quinolin-8-yl)tetrahydro-2H-pyran-4-sulfonamide—Compound (ZDR502)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (55 mg, 0.27 mmol), oxane-4-sulfonyl chloride (50 mg, 0.27 mmol) and triethylamine (38 μL, 0.30 mmol) in dichloromethane (3 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR502) as a pale yellow oil (31 mg, 0.09 mmol, 33%). ¹H NMR (400 MHz, CDCl₃) δ 1.97-2.02 (4H, m), 2.32 (6H, s), 3.20-3.21 (3H, m), 3.75 (2H, s), 3.97-4.01 (2H, m), 7.45-7.49 (1H, m), 7.52-7.55 (1H, m), 7.67 (1H, d, J=8.5 Hz), 7.88 (1H, dd, J=7.5 and 1.5 Hz), 8.15 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₇H₂₃N₃O₃S: 349.1; found [M+H]⁺: 350.2.

Example 210: 1-Cyclopropyl-N-(2-((dimethylamino)methyl)quinolin-8-yl)methanesulfonamide—Compound (ZDR503)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (70 mg, 0.32 mmol), cyclopropylmethanesulfonyl chloride (50 mg, 0.32 mmol) and triethylamine (49 μL, 0.35 mmol) in dichloromethane (3 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR503) as a yellow oil (66 mg, 0.20 mmol, 62%). δ ¹H NMR (400 MHz, CDCl₃) δ 0.12-0.16 (2H, m), 0.52-0.57 (2H, m), 1.10-1.18 (1H, m), 2.31 (6H, s), 3.08 (2H, d, J=7.1 Hz), 3.74 (2H, s), 7.46 (1H, t, J=7.8 Hz), 7.41 (1H, dd, J=8.4 and 1.5 Hz), 7.67 (1H, d, J=8.4 Hz), 7.86 (1H, dd, J=7.5 and 1.5 Hz), 8.14 (1H, d, J=8.4 Hz), 9.09 (1H, brs); ESI-MS: m/z calcd for C₁₆H₂₁N₃O₂S: 319.1; found [M+H]⁺: 320.1.

Example 211: N-(2-((Dimethylamino)methyl)quinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)methanesulfonamide—Compound (ZDR504)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (51 mg, 0.25 mmol), oxan-4-ylmethanesulfonyl chloride (50 mg, 0.25 mmol) and triethylamine (36 μL, 0.27 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 50:1→20:1) afforded compound (ZDR504) as a pale yellow oil (60 mg, 0.17 mmol, 68%). ¹H NMR (400 MHz, CDCl₃) δ 1.30-1.40 (2H, m), 1.76-1.82 (2H, m), 2.24-2.33 (1H, m), 2.33 (6H, s), 3.06 (2H, d, J=6.4 Hz), 3.34-3.38 (2H, m), 3.75 (2H, s), 3.86-3.90 (2H, m), 7.46-7.50 (1H, m), 7.52-7.56 (1H, m), 7.67 (1H, d, J=8.5 Hz), 7.82 (1H, dd, J=7.5 and 1.5 Hz), 8.15 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₈H₂₅N₃O₃S: 363.2; found [M+H]⁺: 364.2.

Example 212: 1-(6-Chloropyridin-3-yl)-N-(2-((dimethylamino)methyl)quinolin-8-yl)methanesulfonamide—Compound (ZDR505)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (45 mg, 0.22 mmol), (6-chloropyridin-3-yl)methanesulfonyl chloride (50 mg, 0.22 mmol) and triethylamine (30 μL, 0.24 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR505) as a pale yellow oil (36 mg, 0.09 mmol, 40%). ¹H NMR (400 MHz, CDCl₃) δ 2.30 (6H, s), 3.65 (2H, s), 4.35 (2H, s), 7.17 (1H, d, J=8.0 Hz), 7.45-7.49 (1H, m), 7.54-7.57 (2H, m), 7.67 (1H, d, J=8.5 Hz), 7.82-7.85 (2H, m), 8.15 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₈H₁₉ClN₄O₂S: 390.1; found [M+H]⁺: 391.1.

Example 213: N-(2-((Dimethylamino)methyl)quinolin-8-yl)prop-2-yne-1-sulfonamide—Compound (ZDR506)

A similar procedure to that described for the preparation of compound (ZDR018) was followed using compound (ZDR059) (73 mg, 0.36 mmol), prop-2-yne-1-sulfonyl chloride (50 mg, 0.36 mmol) and triethylamine (51 μL, 0.39 mmol) in dichloromethane (4 mL). Purification by flash chromatography (dichloromethane/methanol, 20:1) afforded compound (ZDR506) as an orange oil (17 mg, 0.05 mmol, 13%). ¹H NMR (400 MHz, d₆-DMSO) δ 2.75 (1H, s), 3.17 (6H, s), 3.76 (2H, s), 4.64 (2H, s), 7.54-7.56 (1H, m), 7.65-7.74 (3H, m), 8.38 (1H, d, J=8.5 Hz); ESI-MS: m/z calcd for C₁₅H₁₇N₃O₂S: 303.1; found [M+H]⁺: 304.1.

Example 214: Antibacterial Susceptibility and Synergy Determination Methods

Antibacterial susceptibility testing was performed in triplicate (biological) by measuring minimum inhibitory concentrations (MICs) by broth microdilution in 96-well flat bottom microtiter plates (ThermoFisher Scientific, New Zealand). S. uberis ATCC 19436, S. aureus ATCC 6538, or E. coli ATCC 10596 cells grown overnight were diluted to an OD600 of approximately 0.025, so that the final concentration of cells in the MIC assay was approximately 5×10⁵ cfu/mL in media as follows: S. uberis; Todd Hewitt Broth (THB), S. aureus; Tryptic Soy Broth (TSB) and Cation Adjusted Muller Hinton Broth (CAMHB), and E. coli; Lysogeny Borth (LB) and CAMHB, before being dispensed into microtiter wells. As required additional sterile Zinc Sulphate (Heptahydrate) was supplemented into the media, so the final concentration was 50 μM. Test compounds were added to starting wells and two-fold serial dilutions were undertaken to generate a range of inhibitor concentrations at a final volume of 200 μl. Media and test compound-free (untreated) controls were included in each microtiter plate in triplicate. After 24 h incubation at 37° C. and 200 rpm, the OD600 of wells were read using a Varioskan Flash plate reader (ThermoFisher Scientific, New Zealand). The MIC was reported as the lowest concentration of the test compound for which no growth occurred, as determined by OD600 readings. The minimum bactericidal concentration (MBC) was determined using the Miles-Misra drop-plate method to measure the viability of cells in response to test compound challenge.

The MIC and MBC data are shown in Tables 1 and 2.

TABLE 1 Minimum Inhibitory Concentrations (MIC) of Zincaphore (ZDR) molecules S. uberis ATCC S. aureus ATCC E. coli ATCC 19436 MIC 6538 MIC 10536 MIC (μg/ml) (μg/ml) (μg/ml) M No Zinc No Zinc No Zinc Compound (g/mol) Zinc (50 μM) Zinc (50 μM) Zinc (50 μM) ZDR018 366.4 >256 0.125 >256 >256 >256 >256 ZDR019 380.3 16 1 8 8 128 128 ZDR022 409.4 64 0.125 16 8 >256 >256 ZDR022-HCl 445.9 256 0.125 64 4 >256 >256 ZDR024 395.4 64 0.25 16 8 256 ≥256 ZDR025 409.4 64 0.125 32 >256 256 ≥256 ZDR026 423.4 64 0.125 32 >256 >256 >256 ZDR027 423.4 64 0.125 16 16 >256 >256 ZDR028 437.4 128 0.125 256 >256 >256 >256 ZDR029 451.4 >256 0.25 >256 >256 >256 >256 ZDR030 452.5 16 1 16 16 128 ≥256 ZDR031 425.4 16 0.5 32 32 ≥256 >256 ZDR033 449.4 >256 0.125 >256 >256 >256 >256 ZDR035 472.4 2 1 4 4 32 >256 ZDR036 816.8 >256 >256 >256 >256 >256 >256 ZDR037 759.7 >256 2 >256 >256 >256 >256 ZDR041 495.5 >256 0.5 64 >256 >256 >256 ZDR043 439.4 >256 >256 >256 >256 >256 >256 ZDR045 498.4 >256 0.125 >256 >256 >256 >256 ZDR046 453.4 4 1 4 4 >256 >256 ZDR061 341.4 >256 0.25 >256 256 >256 >256 ZDR062 355.4 256 0.25 256 >256 >256 >256 ZDR063 371.4 >256 0.25 >256 >256 >256 >256 ZDR064 375.8 >256 0.0625 128 256 >256 >256 ZDR065 359.4 >256 0.125 256 256 >256 >256 ZDR066 425.4 128 0.0625 256 >256 >256 >256 ZDR067 386.4 128 0.125 128 256 >256 >256 ZDR068 366.4 >256 1 >256 >256 >256 >256 ZDR069 399.4 >256 0.25 256 >256 >256 >256 ZDR070 383.4 >256 0.5 >256 >256 >256 >256 ZDR071 419.5 >256 4 >256 >256 >256 >256 ZDR072 398.4 256 32 >256 >256 >256 >256 ZDR073 384.4 >256 8 >256 >256 >256 >256 ZDR074 409.4 >256 0.0625 >256 >256 256 256 ZDR075 409.4 256 0.125 >256 >256 >256 >256 ZDR076 366.4 >256 1 >256 >256 >256 >256 ZDR077 366.4 >256 1 >256 >256 >256 >256 ZDR078 279.3 >256 2 >256 >256 >256 >256 ZDR079 333.3 >256 0.5 >256 256 >256 64 ZDR080 347.4 >256 0.25 >256 >256 >256 >256 ZDR081 347.4 256 0.25 >256 >256 >256 >256 ZDR082 360.4 >256 0.125 >256 >256 >256 >256 ZDR084 375.8 128 0.0625 256 >256 256 >256 ZDR085 425.4 128 <0.125 256 >256 256 >256 ZDR086 421.4 64 0.25 64 >256 128 256 ZDR087 435.4 256 0.25 128 >256 256 >256 ZDR088 467.5 >256 0.0625 >256 >256 >256 >256 ZDR089 464.5 64 0.5 256 128 >256 >256 ZDR090 466.5 4 0.5 16 16 16 16 ZDR091 439.4 32 0.125 64 32 256 256 ZDR092 455.4 64 16 32 32 >256 >256 ZDR093 455.4 64 16 64 128 256 >256 ZDR094 469.4 32 4 62 32 256 256 ZDR095 486.5 >256 0.125 64 8 128 >256 ZDR096 563.5 64 4 >256 >256 >256 >256 ZDR097 421.4 >256 0.0625 >256 >256 >256 256 ZDR098 419.4 64 0.125 64 >256 >256 >256 ZDR099 427.4 64 0.25 64 >256 >256 256 ZDR100 445.4 128 0.25 32 256 >256 >256 ZDR101 472.4 >256 4 64 64 128 >256 ZDR102 485.4 32 16 32 16 256 64 ZDR103 471.5 >256 0.125 128 >256 >256 >256 ZDR106 461.4 64 0.25 >256 >256 >256 >256 ZDR107 477.5 64 0.125 >256 64 >256 >256 ZDR108 457.4 >256 0.25 64 >256 >256 >256 ZDR109 458.4 >256 0.5 >256 >256 >256 >256 ZDR110 472.4 >256 4 >256 >256 >256 >256 ZDR111 492.5 8 0.5 16 16 64 >256 ZDR112 494.5 64 1 16 32 >256 >256 ZDR113 510.5 128 1 >256 >256 >256 >256 ZDR114 701.6 32 4 64 64 64 64 ZDR115 700.6 4 2 16 16 16 16 ZDR116 508.5 32 2 64 64 >256 >256 ZDR117 715.6 16 4 64 64 128 32 ZDR118 437.4 32 2 128 8 >256 >256 ZDR119 566.6 4 0.125 4 4 >256 >256 ZDR120 436.4 32 0.5 16 16 >256 >256 ZDR121 499.5 32 2 16 16 >256 >256 ZDR122 499.5 32 2 16 16 >256 >256 ZDR123 605.6 >256 0.125 >256 >256 >256 >256 ZDR124 602.5 32 16 16 16 128 32 ZDR125 395.4 8 0.125 4 4 >256 >256 ZDR126 409.4 >256 0.125 >256 >256 >256 >256 ZDR127 394.4 >256 1 16 16 >256 >256 ZDR129 469.4 64 1 32 32 256 256 ZDR130 513.5 64 1 128 256 256 256 ZDR131 483.5 64 1 64 128 256 256 ZDR132 527.5 64 1 64 256 256 256 ZDR133 439.4 64 0.25 64 256 >256 256 ZDR135 437.4 128 0.25 32 64 >256 >256 ZDR136 465.5 >256 8 >256 >256 >256 >256 ZDR137 485.5 >256 0.125 >256 >256 >256 >256 ZDR138 484.5 >256 0.5 128 128 >256 >256 ZDR139 666.7 64 0.125 256 256 >256 >256 ZDR143 660.5 8 4 8 8 16 16 ZDR145 511.5 >256 >256 64 128 128 256 ZDR148 466.5 64 1 64 128 128 256 ZDR153 408.4 >256 0.5 64 64 >256 >256 ZDR154 420.5 >256 16 >256 >256 >256 >256 ZDR155 420.5 >256 >256 >256 >256 >256 >256 ZDR160 356.4 256 >256 >256 >256 >256 >256 ZDR162 356.4 256 16 >256 >256 >256 >256 ZDR163 357.4 >256 8 >256 >256 >256 >256 ZDR164 357.4 >256 >256 >256 >256 >256 >256 ZDR167 524.5 2 0.5 2 2 >256 >256 ZDR170 518.5 8 1 8 4 256 256 ZDR171 473.5 8 0.5 4 4 >256 >256 ZDR176 382.4 >256 0.5 4 4 >256 >256 ZDR180 502.4 >256 0.5 64 256 128 >256 ZDR181 564.5 >256 0.5 64 >256 64 >256 ZDR184 381.4 32 0.5 8 4 64 128 ZDR185 423.5 >256 0.125 256 32 >256 >256 ZDR186 623.6 >256 0.25 >256 >256 >256 >256 ZDR187 408.4 16 0.5 8 8 32 16 ZDR188 468.4 >256 0.5 >256 >256 >256 >256 ZDR190 375.9 256 1 >256 >256 >256 >256 ZDR191 425.4 256 0.125 >256 >256 >256 >256 ZDR192 350.4 >256 1 >256 >256 >256 >256 ZDR193 348.5 128 0.25 >256 >256 >256 >256 ZDR194 345.4 >256 4 >256 >256 >256 >256 ZDR195 345.4 >256 32 >256 >256 >256 >256 ZDR196 399.5 256 0.0625 >256 32 >256 >256 ZDR201 359.4 128 0.0625 >256 32 >256 >256 ZDR202 420.3 256 0.125 256 >256 >256 >256 ZDR203 376.5 256 0.5 >256 64 >256 >256 ZDR204 334.4 256 0.5 >256 256 >256 >256 ZDR205 563.5 256 0.125 128 64 >256 >256 ZDR209 459.5 >256 1 >256 >256 >256 >256 ZDR210 521.5 >256 0.25 >256 >256 >256 >256 ZDR211 591.5 64 16 128 64 128 128 ZDR224 577.5 64 16 128 32 256 256 ZDR257 387.5 >256 0.0625 >256 >256 >256 >256 ZDR258 372.4 256 0.125 >256 >256 >256 >256 ZDR259 305.4 >256 0.25 >256 256 >256 >256 ZDR261 717.6 32 16 32 32 64 64 ZDR262 757.7 8 16 64 128 32 64 ZDR263 542.5 >256 256 >256 >256 >256 >256 ZDR265 639.5 128 256 64 64 256 256 ZDR266 535.4 16 16 64 32 128 256 ZDR267 551.4 256 256 256 128 >256 >256 ZDR268 703.6 32 16 64 128 64 64 ZDR269 743.6 4 8 32 64 64 64 ZDR270 549.5 16 4 32 32 128 256 ZDR305 420.3 >256 0.0625 64 128 >256 >256 ZDR306 407.4 128 0.125 128 128 >256 >256 ZDR307 397.5 >256 0.0625 >256 >256 >256 >256 ZDR308 399.5 256 0.25 256 >256 256 >256 ZDR309 420.3 128 0.125 64 128 >256 >256 ZDR310 419.5 256 4 >256 >256 >256 >256 ZDR311 383.5 256 0.0625 >256 256 >256 >256 ZDR312 359.4 128 0.125 256 256 >256 >256 ZDR313 386.4 128 0.25 128 >256 >256 >256 ZDR314 371.5 128 0.25 256 >256 >256 >256 ZDR315 355.5 >256 0.25 256 >256 >256 >256 ZDR316 361.4 >256 0.125 >256 >256 >256 >256 ZDR317 355.5 256 0.25 >256 128 >256 >256 ZDR318 307.4 256 32 >256 >256 >256 >256 ZDR319 405.5 >256 1 >256 >256 >256 >256 ZDR320 423.5 256 0.0625 >256 128 >256 >256 ZDR321 321.4 256 0.25 >256 128 >256 >256 ZDR322 376.9 >256 0.25 128 >256 >256 >256 ZDR323 305.4 >256 1 >256 256 >256 >256 ZDR324 369.4 256 1 256 256 >256 >256 ZDR326 381.9 128 0.125 32 128 256 >256 ZDR327 398.5 256 8 >256 >256 >256 >256 ZDR328 342.4 >256 1 >256 >256 >256 >256 ZDR330 441.5 128 0.125 32 32 >256 >256 ZDR331 384.5 >256 16 >256 >256 >256 >256 ZDR332 414.5 256 2 >256 >256 >256 >256 ZDR333 456.6 64 0.125 128 128 >256 >256 ZDR335 410.3 64 0.0312 32 8 >256 >256 ZDR336 410.3 64 0.0625 64 128 >256 >256 ZDR337 395.4 256 0.0625 >256 >256 >256 >256 ZDR338 377.4 128 0.0625 >256 >256 >256 >256 ZDR339 392.5 256 2 >256 >256 >256 >256 ZDR340 392.5 64 0.25 >256 32 >256 >256 ZDR401 437.5 16 0.125 32 128 64 >256 ZDR402 437.5 16 0.125 32 128 256 >256 ZDR403 437.5 16 0.125 32 128 64 256 ZDR404 449.5 16 0.125 32 256 128 >256 ZDR405 463.5 16 0.125 64 128 128 >256 ZDR406 477.5 16 0.125 32 128 64 256 ZDR407 435.5 128 0.125 64 256 256 256 ZDR408 463.5 32 0.125 64 256 >256 256 ZDR409 465.5 256 0.125 64 256 >256 >256 ZDR500 291.4 >256 0.5 256 >256 >256 >256 ZDR501 360.4 >256 0.25 256 >256 >256 >256 ZDR502 349.4 >256 0.25 >256 >256 >256 >256 ZDR503 319.4 >256 0.125 >256 256 >256 >256 ZDR504 363.5 >256 0.5 >256 256 >256 >256 ZDR505 390.9 >256 0.25 >256 256 >256 >256 ZDR506 303.4 256 2 >256 >256 >256 >256

TABLE 2 Bactericidal (MBC) activity of selected Zincaphore (ZDR) molecules S. uberis ATCC S. aureus ATCC E. coli ATCC 19436 MBC 6538 MBC 10536 MBC (μg/ml) (μg/ml) (μg/ml) M No Zinc No Zinc No Zinc Compound (g/mol) Zinc (50 μM) Zinc (50 μM) Zinc (50 μM) ZDR022-HCl 445.9 >256 0.125 128 256 >256 >256 ZDR090 466.5 8 0.5 16 32 16 16 ZDR091 439.4 16 0.5 >256 128 256 128 ZDR092 455.4 64 8 256 32 256 >256 ZDR095 486.5 >256 1 >128 >256 128 256 ZDR102 485.4 32 16 128 32 256 >256 ZDR111 492.5 8 1 16 16 >256 >256 ZDR112 494.5 64 2 >256 256 128 >256 ZDR114 701.6 32 4 128 64 >256 64 ZDR115 700.6 8 4 16 16 16 16 ZDR116 508.5 64 2 128 >256 >256 >256 ZDR117 715.6 16 4 64 64 256 64 ZDR119 566.6 16 1 >256 32 >256 >256 ZDR120 436.4 >256 1 >256 >256 >256 >256 ZDR121 499.5 256 32 64 256 >256 >256 ZDR122 499.5 128 32 32 128 >256 >256 ZDR124 602.5 16 16 >256 >256 128 32 ZDR125 395.4 8 0.5 >256 >256 >256 >256 ZDR127 394.4 >256 2 >256 >256 >256 >256 ZDR143 660.5 8 8 16 16 32 32 ZDR167 524.5 8 0.5 8 8 >256 >256 ZDR170 518.5 16 2 128 128 >256 >256 ZDR171 473.5 8 0.5 16 32 >256 >256 ZDR187 408.4 16 8 32 32 64 16 ZDR224 577.5 64 8 128 32 >256 256 ZDR261 717.6 16 16 128 64 >256 >256 ZDR269 743.6 4 16 64 128 64 64 ZDR335 410.3 64 2 >256 >256 >256 >256

Although the invention has been described by way of example, it should be appreciated that variations and modifications may be made without departing from the scope of the invention as defined in the claims. Furthermore, where known equivalents exist to specific features, such equivalents are incorporated as if specifically referred in this specification. 

The invention claimed is:
 1. A compound of Formula I:

wherein R₁ is selected from the group comprising: saturated or unsaturated C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ cycloalkyl, C₃-C₆ cycloalkylmethyl, phenyl or benzyl optionally substituted with one or more halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, OR₃, SR₃, SO₂R₃, SO₂NR₃R₄, NR₃R₄, NR₃CO₂R₄, NO₂, CN, CHO, COR₃, CO₂R₃ or CONR₃R₄, 5- or 6-membered heterocyclyl or heterocyclylmethyl, 5- or 6-membered heteroaryl optionally substituted with one or more halogen, hydroxy, OR₃, C₁-C₆ alkyl or CO₂R₃, and 5- or 6-membered heteroarylmethyl optionally substituted with one or more halogen or C₁-C₆ alkyl; R₂ is selected from the group comprising C₁-C₆ alkyl(heterocyclyl), (C₁-C₆ alkyl)NR₇R₈, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₈R₉, (C₁-C₆ alkyl)N((C₁-C₆ alkyl)NR₈R₉)₂, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)OR₈, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)O(C₁-C₆ alkyl)OR₈, (C₁-C₆ alkyl)NR₇C(═O)R₈, (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)C(═O)NR₈R₉, (C₁-C₆alkyl)NR₃C(═NNO₂)NR₄R₅, (C₁-C₆ alkyl)NR₃C(═NR₄)NR₅R₆, (C₁-C₆ alkyl)NR₃C(═NR₄)R₅, (C₁-C₆ alkyl)NR₃SO₂R₄, (C₀-C₃ alkyl)CH═NOR₇, (C₀-C₃ alkyl)CH═NNR₇R₈, (C₀-C₃ alkyl)CH═NNR₃C(═O)R₇, (C₀-C₃ alkyl)CH═NNR₃C(═S)R₇, (C₀-C₃ alkyl)CH═NNR₃C(═O)NR₇R₈, (C₀-C₃ alkyl)CH═NNR₃C(═S)NR₇R₈, (C₀-C₃ alkyl)C(═O)NR₇R₈, (C₀-C₃ alkyl)C(═O)NR₃OR₇, (C₀-C₃ alkyl)C(═O)NR₃NR₇R₈; provided that R₁ is not methyl or ethyl when R₂ is a methyl(heterocyclyl) group; R₃, R₄, R₅ and R₆ are each selected from the group comprising hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and aryl; and R₇, R₈ and R₉ are each selected from the group comprising hydrogen, saturated or unsaturated C₁-C₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁-C₆ alkyl(cycloalkyl), aralkyl, C₁-C₆ alkyl(heterocyclyl), C₁-C₆ alkyl(heteroaryl), each of which is optionally substituted with one or more of halogen, OR₃, NR₃R₄, NR₃COR₄, NR₃C(═NR₄)NR₅R₆, NR₃C(═NNO₂)NR₄R₅, NR₃SO₂R₄, NO₂, and CO₂R₃; or a pharmaceutically acceptable salt or hydrate thereof.
 2. A compound as claimed in claim 1 wherein R₁ is C₁-C₆ alkyl or C₁-C₆ haloalkyl, or R₁ is phenyl, benzyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with halogen, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy.
 3. A compound as claimed in claim 1 wherein R₁ is (trifluoromethyl)phenyl.
 4. A compound as claimed in claim 1 wherein R₂ is: (i) (C₁-C₆ alkyl)NR₇R₈; (ii) (C₁-C₆ alkyl)NR₇(C₁-C₆ alkyl)NR₈R₉; (iii) (C₀-C₃ alkyl)CH═NOR₇; (iv) (C₀-C₃ alkyl)CH═NNR₇R₈; (v) (C₀-C₃ alkyl)CH═NNR₃C(═O)R₇; (vi) (C₀-C₃ alkyl)CH═NNR₃C(═O)NR₇R₈; or (vii) (C₀-C₃ alkyl)CH═NNR₃C(═S)NR₇R₈.
 5. A compound as claimed in claim 1, which is selected from the group comprising:


6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 7. A composition as claimed in claim 6 which is a veterinary pharmaceutical composition.
 8. A composition as claimed in claim 6 further comprising an antimicrobial compound selected from the group comprising chlorhexidine, iodine, lactic acid, cetrimide, BZK (benzylalkonium chloride), amoxicillin, erythromycin, cloxacillin, pirlimycin, cephapirin, hetacillin, penicillin, nicin and lacticin.
 9. A composition as claimed in claim 6 which is formulated as a tablet, capsule or powder, or as a solution, suspension or dispersion for oral, injectable or sprayable administration.
 10. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.
 11. A composition as claimed in claim 10 which is a veterinary pharmaceutical composition.
 12. A method of treating or preventing a bacterial infection in an animal comprising administering to an animal a pharmaceutically effective amount of a compound of claim
 1. 13. A method of treating or preventing a bacterial infection in an animal comprising administering to an animal a pharmaceutically effective amount of a compound of claim
 5. 14. A method as claimed in claim 13 wherein the bacterial infection is caused by Streptococcus uberis, Staphylococcus aureus, Staphylococcus agalactiae or Escherichia coli.
 15. A method as claimed in claim 12 wherein the animal is a bovine cow. 